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Knockdown of interferon-induced transmembrane protein 1 inhibited proliferation, induced cell cycle arrest and apoptosis, and suppressed MAPK signaling pathway in pancreatic cancer cells
Abstract
Pancreatic cancer (PC), highly malignant, is one of the most lethal cancers. Interferon-induced transmembrane protein 1 (IFITM1) has recently been regarded as a new molecular marker in human cancers. However, the role of IFITM1 in PC remains unclear. In this study, a short hairpin RNA (shRNA) was constructed to assess the effect of IFITM1 on PANC-1 and ASPC-1 cells. The level of IFITM1 was downregulated in cells transfected with shRNA targeting IFITM1 (sh-IFITM1). Silencing of IFITM1 significantly decreased cell viability, downregulated the level of Ki-67, arrested cell at G1/S phase, reduced the number of cells in S phase, and decreased cyclinD1, cyclinE, CDK2, and CDK4 levels. Moreover, Hoechst staining and Western blotting analysis showed that cell apoptosis was induced by IFITM1. IFITM1 knockdown suppressed the MAPK signaling pathway by downregulation of p-ERK, p-P38, and p-JNK levels. These findings suggested that IFITM1 could be considered a potential therapeutic target for PC.
... Some mesenchymal tissue-derived cancers such as glioma [28,29], osteosarcoma [30], and myeloid leukemia [31][32][33] also show IFITM1, IFITM2, or IFITM3 overexpressed in these cancers. However, the IFITMs expression in pancreatic cancer are rarely reported in the literature and just reported the IFITM1 was highly expressed in pancreatic cancer [34][35][36]. We analyzed IFITM1-3 mRNA expression difference in pancreatic cancer and adjacent tissues according to TCGA and GTEx database. ...
... Asona et al. found that IFITM1 promoted breast cancer cell survival by inhibiting the p21 transcription, expression, and nuclear localization mediated by the JAK/STAT pathway [25]. Recently, Lei et al. reported that IFITM1 knockdown suppressed the MAPK signaling pathway to inhibit the pancreatic cancer cells proliferation, and silencing of IFITM1 also decreased cyclinD1, CDK2, and CDK4 levels [36]. ...
... In conclusion, we elucidate the signal pathways of IFITM1-3 promoting cancer proliferation from the JAK/ STAT pathway [25], CCND1-CDK4/6-pRB axis [36,39], MAPK [12,36] pathway, or PI3K/AKT/mTOR [27] pathway (Fig. 2). So, which role do IFITM2 or IFITM3 play in pancreatic cancer growth? ...
Human interferon-induced transmembrane protein family (IFITMs) consists of five main proteins. IFITM1, IFITM2, and IFITM3 can be induced by interferon, while IFITM5 and IFITM10 are insensitive to interferon. IFITMs has various functions, including well-researched antiviral effects. As a molecule whose expression is significantly increased by interferon in the immune microenvironment, IFITMs has drawn growing interest in recent years for their role in the cancer progression. Unlike antiviral effects, the role and mechanism of IFITMs in cancer progression have not been clearly studied, especially the role and molecular mechanism of IFITMs in pancreatic cancer are rarely reported in the literature. This article focuses on the role and potential mechanism of IFITMs in pancreatic cancer progression by analyzing the function and mechanism of IFITM1-3 in other cancers and conducting bioinformatics analysis using the databases, so as to provide a new target for pancreatic cancer therapy.
... There are some other evidence suggest that IFITM1 could promote the activation of MAPK. For instance, Lei Zhang and colleagues found that knockdown of IFITM1 in human pancreatic cancer cells suppresses the MAPK signaling 43) . Besides, Weiyu Zhang and colleagues noticed the alteration of MAPK's activation mediated by IFITM1 44) . ...
Dental pulp stem cells (DPSCs) invoke wide interest due to their roles in in dentin regeneration and repair, and more research is required to illustrate the molecular basis. In this study, we induced osteogenic differentiation in human DPSCs to investigate the role of interferon-induced transmembrane (IFITM) family in osteogenic differentiation. Our results demonstrated that genes of the IFITM family, IFITM1, IFITM3, and IFITM5 were upregulated during the osteogenic differentiation of DPSCs. Loss-of-function and gain-of-function assays indicated that IFITM3 knockdown suppressed osteogenic differentiation, assessed by the reduction of alkaline phosphatase (ALP) activity, nodule mineralization, and the expressions of several osteogenic differentiation-associated genes; in contrast, IFITM3 overexpression increased ALP activity, nodule mineralization, and the expressions of osteogenic differentiation-associated genes. Further investigation revealed that IFITM3 was involved in the regulation of mitogen-activated protein kinase (MAPK) signaling during osteogenic differentiation, and pharmacological inhibition of both ERK and p38 suppressed the effects of IFITM3 overexpression in osteogenic differentiation. These results suggest that IFITM3 promotes osteogenic differentiation of DPSCs by regulating MAPK signaling. Our findings enhance the existing knowledge on the role of IFITM family in osteogenic differentiation and the molecular basis of IFITM3.
... And plays a key role in the antiproliferative action of IFN-gamma either by inhibiting the ERK activation or by arresting cell growth in the G1 phase in a p53-dependent manner. It has been shown that IFITM1 is tightly regulated by the proliferation, migration, and invasion of breast cancer and inhibits apoptosis, and that inhibition of IFITM1 expression by disrupting interferon-α and NF-κB crosstalk can attenuate triple-negative breast cancer progression [19,20], which may be one of the novel immunomarkers for endometrial cancer stromal cells [20], and knockdown of IFITM1 in pancreatic cancer was also found to inhibit the proliferation of cells, that induced cell cycle arrest and apoptosis, and inhibited cancer progression [21]. In smallcell lung cancer, IFITM1 overexpression was found to promote distant metastasis, and in lung adenocarcinoma, IFITM1 expression was found to be significantly associated with increased microvessel density and correlated with patient prognosis [22]. ...
Objective
To explore dermatomyositis signature genes as potential biomarkers of hepatocellular carcinoma and their associated molecular regulatory mechanisms.
Methods
Based on the mRNA-Seq data of dermatomyositis and hepatocellular carcinoma in public databases, five dermatomyositis signature genes were screened by LASSO regression analysis and support vector machine (SVM) algorithm, and their biological functions in dermatomyositis with hepatocellular carcinoma were investigated, and a nomogram risk prediction model for hepatocellular carcinoma was constructed and its predictive efficiency was initially evaluated. The immune profile in hepatocellular carcinoma was examined based on the CIBERSORT and ssGSEA algorithms, and the correlation between five dermatomyositis signature genes and tumor immune cell infiltration and immune checkpoints in hepatocellular carcinoma was investigated.
Results
The expression levels of five dermatomyositis signature genes were significantly altered in hepatocellular carcinoma and showed good diagnostic efficacy for hepatocellular carcinoma, suggesting that they may be potential predictive targets for hepatocellular carcinoma, and the risk prediction model based on five dermatomyositis signature genes showed good risk prediction efficacy for hepatocellular carcinoma and has good potential for clinical application. In addition, we also found that the upregulation of SPP1 expression may activate the PI3K/ART signaling pathway through integrin-mediated activation, which in turn regulates the development and progression of hepatocellular carcinoma.
Conclusion
LY6E, IFITM1, GADD45A, MT1M, and SPP1 are potential predictive targets for new-onset hepatocellular carcinoma in patients with dermatomyositis, and the upregulation of SPP1 expression may activate the PI3K/ART signaling pathway through the mediation of integrins to promote the development and progression of hepatocellular carcinoma.
Interferons (IFNs) are important cytokines that regulate immune responses through the activation of hundreds of genes, including interferon-induced transmembrane proteins (IFITMs). This evolutionarily conserved protein family includes five functionally active homologs in humans. Despite the high sequence homology, IFITMs vary in expression, subcellular localization and function. The initially described adhesive and antiproliferative or pro-oncogenic functions of IFITM proteins were diluted by the discovery of their antiviral properties. The large set of viruses that is inhibited by these proteins is constantly expanding, as are the possible mechanisms of action. In addition to their beneficial antiviral effects, IFITM proteins are often upregulated in a broad spectrum of cancers. IFITM proteins have been linked to most hallmarks of cancer, including tumor cell proliferation, therapeutic resistance, angiogenesis, invasion, and metastasis. Recent studies have described the involvement of IFITM proteins in antitumor immunity. This review summarizes various levels of IFITM protein regulation and the physiological and pathological functions of these proteins, with an emphasis on tumorigenesis and antitumor immunity.
Background and aims:
Hepatocellular carcinoma (HCC) is listed as one of the most common causes of cancer-related death. Oncolytic therapy has become a promising treatment because of novel immunotherapies and gene editing technology, but biosafety concerns remain the biggest limitation for clinical application. We studied the the antitumor activity and biosafety of the wild-type Newcastle disease virus HK84 strain (NDV/HK84) and 10 other NDV strains.
Methods:
Cell proliferation and apoptosis were determined by cell counting Kit-8 and fluorescein isothiocyanate Annexin V apoptosis assays. Colony formation, wound healing, and a xenograft mouse model were used to evaluate in vivo and in vitro oncolytic effectiveness. The safety of NDV/HK84 was tested in nude mice by an in vivo luciferase imaging system. The replication kinetics of NDV/HK84 in normal tissues and tumors were evaluated by infectious-dose assays in eggs. RNA sequencing analysis was performed to explore NDV/HK84 activity and was validated by quantitative real-time PCR.
Results:
The cell counting Kit-8 assays of viability found that the oncolytic activity of the NDV strains differed with the multiplicity of infection (MOI). At an MOI of 20, the oncolytic activity of all NDV strains except the DK/JX/21358/08 strain was >80%. The oncolytic activities of the NDV/HK84 and DK/JX/8224/04 strains were >80% at both MOI=20 and MOI=2. Only NDV/HK84 had >80% oncolytic activities at both MOI=20 and MOI=2. We chose NDV/HK84 as the candidate virus to test the oncolytic effect of NDV in HCC in the in vitro and in vivo experiments. NDV/HK84 killed human SK-HEP-1 HCC cells without affecting healthy cells.
Conclusions:
Intratumor infection with NDV/HK84 strains compared with vehicle controls or positive controls indicated that NDV/HK84 strain specifically inhibited HCC without affecting healthy mice. High-throughput RNA sequencing showed that the oncolytic activity of NDV/HK84 was dependent on the activation of type I interferon signaling.
Breast cancer is the current leading cause of cancer death in females worldwide. Although current chemotherapeutic drugs effectively reduce the progression of breast cancer, most of these drugs have many unwanted side effects. Salvianolic acid B (Sal-B) is a bioactive compound isolated from the root of Danshen Radix with potent antioxidant and anti-inflammatory properties. Since free radicals play a key role in the initiation and progression of tumor cells growth and enhance their metastatic potential, the current study was designed to investigate the antitumor activity of Sal-B and compare it with the antitumor activity of the traditional anticancer drug, cisplatin. In vitro, Sal-B decreased the human breast cancer adenocarcinoma (MCF-7) cells proliferation in a concentration and time dependent manner. In vivo and similar to cisplatin treatment, Sal-B significantly reduced tumor volume and increased the median survival when compared to tumor positive control mice group injected with Ehrlich solid carcinoma cell line (ESC). Sal-B decreased plasma level of malondialdehyde as a marker of oxidative stress and increased plasma level of reduced glutathione (GSH) as a marker of antioxidant defense when compared to control ESC injected mice. Either Sal-B or cisplatin treatment decreased tumor tissue levels of tumor necrosis factor (TNF-α), matrix metalloproteinase-8 (MMP-8), and Cyclin D1 in ESC treated mice. Contrary to cisplatin treatment, Sal-B did not decrease tumor tissue Ki-67 protein in ESC injected mice. Immunohistochemical analysis revealed that Sal-B or cisplatin treatment increased the expression of the apoptotic markers caspase-3 and P53. Although Sal-B or cisplatin significantly reduced the expression of the angiogenic factor vascular endothelial growth factor (VEGF) in ESC injected mice, only Sal-B reduced expression level of COX-2 in ESC injected mice. Our data suggest that Sal-B exhibits antitumor features against breast cancer cells possibly via enhancing apoptosis and reducing oxidative stress, inflammation, and angiogenesis.
Pancreatic cancer (PDAC) is a highly invasive cancer with poor prognosis. Recent research has found that the transcription factor Yin Yang 1 (YY1) plays an inhibitory role in the development of pancreatic cancer. It has been reported that tubulin polymerisation-promoting protein (TPPP) plays an indispensable role in a variety of tumours, but its expression and role in pancreatic cancer have not yet been elucidated.
In this study, we performed ChIP-sequencing and found that YY1 directly binds to the promoter region of TPPP. The expression of TPPP in pancreatic cancer was detected by western blotting and immunohistochemistry. Four-week-old male BALB/c-nude mice were used to assess the effect of TPPP on pancreatic cancer.
Immunohistochemistry revealed that TPPP was expressed at low levels in pancreatic cancer tissues, and was associated with blood vessel invasion. The results from vivo experiments have showed that TPPP could enhance the migration and invasion of pancreatic cancer. Further experiments showed that YY1 could inhibit the migration, invasion and angiogenesis of pancreatic cancer cells by downregulating TPPP via p38/MAPK and PI3K/AKT pathways.
Our study demonstrates that TPPP may act as a promoter and may serve as a novel target for the treatment of pancreatic cancer.
Background:
FDG-PET might be able to reflect histopathology features of tumors. Ki 67 in head and neck carcinomas (HNSCC). The present study sought to elucidate the association between Ki 67 index and SUVmax based upon a large patient sample.
Methods:
PubMed database was screened for studies analyzed the relationship between Ki 67 and SUV in HNSCC. Nine studies comprising 211 patients were suitable for analysis.
Results:
SUVmax increased with tumor grade and was statistically significant different between G1, G2, and G3 tumors. The ROC analysis for discrimination between G1/G2 and G3 tumors revealed an area under curve of 0.71. In the overall patient sample, SUVmax correlated statistically significant with Ki 67 index (r = 0.154, P = .032).
Conclusion:
The present study identified a weak correlation between SUV values and proliferation index Ki 67 index in HNSCC in a large patient sample. Therefore, SUVmax cannot be used as surrogate parameter for proliferation activity in HNSCC.
Curcumin has been demonstrated to reduce markers of inflammation during acute pancreatitis (AP). However, the underlying mechanisms of the protective effects of curcumin are unknown. In the present study the effects of curcumin in an AP animal model and cell models was examined and the underlying mechanisms were investigated. An AP animal model was established by injection of 5% sodium taurocholate into the biliopancreatic duct of rats, and the cell model was established by treatment with 0.5 nM cerulein with an optimal concentration of lipopolysaccharide in AR42J rat pancreatic cancer cells. Amylase activity and arterial blood gas composition were assessed by automatic biochemical and blood gas analyzers. Pathological alteration of the pancreas was determined by hematoxylin and eosin staining. Interleukin (IL‑6), tumor necrosis factor (TNF)‑α and C‑reactive protein (CRP) levels were measured by ELISA. Cell viability was determined by Cell Counting Kit‑8 and protein expression levels were assessed by western blotting. Curcumin reduced the ascites volume after 12 and 24 h, the weight of pancreas after 12, 24 and 36 h of surgery, but also attenuated injury to the pancreas. Serum expression levels of TNF‑α and CRP were reduced by curcumin. In addition, curcumin decreased the cell viability, amylase activity and the phosphorylation of p38 in AR42J cells, but did not affect the intracellular levels of IL‑6 and TNF‑α. Curcumin may lower the severity and inflammatory response via the mitogen‑activated protein kinase‑signaling pathway, to some extent. However, future studies are required to fully understand the protective effects of curcumin on AP.
Piperlongumine (PL) is an alkaloid that inhibits glutathione S-transferase pi 1 (GSTP1) activity, resulting in elevated reactive oxygen species (ROS) levels and cancer-selective cell death. We aimed to identify stress-associated molecular responses to PL treatment in pancreatic ductal adenocarcinoma (PDAC) cells. GSTP1 directly interacts with JNK, which is activated by oxidative stress and can lead to decreased cancer cell proliferation and cell death. Therefore, we hypothesized that JNK pathways are activated in response to PL treatment. Our results show PL causes dissociation of GSTP1 from JNK; robust JNK, c-Jun, and early ERK activation followed by suppression; increased expression of cleaved caspase-3 and cleaved PARP; and nuclear translocation of Nrf2 and c-Myc in PDAC cells. Gene expression analysis revealed PL caused a > 20-fold induction of heme oxygenase-1 (HO-1), which we hypothesized was a survival mechanism for PDAC cells under enhanced oxidative stress. HO-1 knockout resulted in enhanced PL-induced PDAC cell death under hypoxic conditions. Similarly, high concentrations of the HO-1 inhibitor, ZnPP (10 µM), sensitized PDAC cells to PL; however, lower concentrations ZnPP (10 nM) and high or low concentrations of SnPP both protected PDAC cells from PL-induced cell death. Interestingly, the JNK inhibitor significantly blocked PL-induced PDAC cell death, Nrf-2 nuclear translocation, and HMOX-1 mRNA expression. Collectively, the results demonstrate JNK signaling contributes to PL-induced PDAC cell death, and at the same time, activates Nrf-2 transcription of HMOX-1 as a compensatory survival mechanism. These results suggest that elevating oxidative stress (using PL) while at the same time impairing antioxidant capacity (inhibiting HO-1) may be an effective therapeutic approach for PDAC.
Interferon-induced transmembrane protein 1 (IFITM1), a 17-kDa membrane protein, is generally known as a modulator in many cellular functions. Recent studies showed overexpression of IFITM1 in cancers and relationship between IFITM1 overexpression and tumor progression. However, the role of IFITM1 in lung cancer remains unclear. Here, we presented the overexpression of IFITM1 in lung cancer tissues and cell lines A549 and H460 using quantitative Real-Time RT-PCR. In vitro assay indicated IFITM1 silencing inhibited lung cancer cell proliferation, migration, and invasion. Further, in vivo assay showed that IFITM1 silencing markedly suppressed cell growth and metastasis of lung cancer in tumor-bearing BALB/c nude mice. Mechanistically, we found that IFITM1 silencing significantly alleviated the protein levels of β -catenin, cyclin D1, and c-Mycin lung cancer cells and tumor samples. Taken together, our study revealed the role of IFITM1 as a tumor promoter during lung cancer development and the possible molecular mechanism.
Background/aim:
Piperine is a major pungent alkaloid present in black pepper (Piper nigrum L). This study investigated the potential anticancer effects of piperine on human melanoma cells and explored the potential pharmacological mechanisms in vitro and in vivo.
Materials and methods:
Studies were performed using the MTT assay, 4',6-diamidino-2-phenylindole (DAPI) staining, western blotting, a xenograft model, the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and immunohistochemistry.
Results:
Piperine inhibited the growth of melanoma cells. Several apoptotic events were observed following treatment, as revealed by DAPI staining. Piperine increased the expression of BCL2-associated X, apoptosis regulator (BAX), cleaved poly(ADP-ribose)polymerase, cleaved caspase-9, phospho-c-Jun N-terminal kinase and phospho-p38, and reduced that of B-cell lymphoma 2 (BCL2), X-chromosome-linked inhibitor of apoptosis, and phospho-extracellular signal-regulated protein kinase (ERK1/2) in a concentration-dependent manner. Treatment of mice for 4 weeks with piperine inhibited tumor growth without apparent toxicity. Piperine increased the expression of apoptotic cells and cleaved-caspase-3 protein and reduced the expression of phospho-ERK1/2 protein in melanoma tumors.
Conclusion:
Piperine suppressed the growth of human melanoma cells by the induction of apoptosis via the inhibition of tumor growth of human melanoma cells and tumor xenograft models.
Pancreatic cancer is one of the most malignant tumors. Invasion and metastasis can occur in the early stage of pancreatic cancer, contributing to the poor prognosis. Accordingly, in this study, we evaluated the molecular mechanisms underlying invasion and metastasis. Using mass spectrometry, we found that Integrin alpha 6 (ITGA6) was more highly expressed in a highly invasive pancreatic cancer cell line (PC-1.0) than in a less invasive cell line (PC-1). Through in vitro and in vivo experiments, we observed significant decreases in invasion and metastasis in pancreatic cancer cells after inhibiting ITGA6. Based on data in TCGA, high ITGA6 expression significantly predicted poor prognosis. By using Co-IP combined mass spectrometry, we found that ribosomal protein SA (RPSA), which was also highly expressed in PC-1.0, interacted with ITGA6. Similar to ITGA6, high RPSA expression promoted invasion and metastasis and indicated poor prognosis. Interestingly, although ITGA6 and RPSA interacted, they did not mutually regulate each other. ITGA6 and RPSA affected invasion and metastasis via the PI3K and MAPK signaling pathways, respectively. Inhibiting ITGA6 significantly reduced the expression of p-AKT, while inhibiting RPSA led to the downregulation of p-ERK1/2. Compared with the inhibition of ITGA6 or RPSA alone, the downregulation of both ITGA6 and RPSA weakened invasion and metastasis to a greater extent and led to the simultaneous downregulation of p-AKT and p-ERK1/2. Our research indicates that the development of drugs targeting both ITGA6 and RPSA may be an effective strategy for the treatment of pancreatic cancer.
Pancreatic cancer (PC) is one of the most lethal diseases, characterized by early metastasis and high mortality. Subunits of the SWI/SNF complex have been identified in many studies as the regulators of tumor progression, but the role of SMARCAD1, one member of the SWI/SNF family, in pancreatic cancer has not been elucidated. Based on analysis of GEO database and immunohistochemical detection of patient-derived pancreatic cancer tissues, we found that SMARCAD1 is more highly expressed in pancreatic cancer tissues and that its expression level negatively correlates with patients' survival time. With further investigation, it shows that SMARCAD1 promotes the proliferation, migration, invasion of pancreatic cancer cells. Mechanistically, we first demonstrate that SMARCAD1 induces EMT via activating Wnt/β-catenin signaling pathway in pancreatic cancer. Our results provide the role and potential mechanism of SMARCAD1 in pancreatic cancer, which may prove useful marker for diagnostic or therapeutic applications of PC disease.
Objective
Pancreatic carcinoma (PC), one of the most prevalent and malignant tumors, has a poor prognosis and a high mortality rate. EG-VEGF, a vascular endothelial growth factor from endocrine glands, also termed as PROK1, has a high positive expression rate in PC tissues and is involved in the pathogenesis of various tumors. However, the expression and potential role of EG-VEGF in PC has not been thoroughly explored. The aim of this study was to better clarify the expression and potential role of EG-VEGF in pancreatic carcinoma.
Methods
Immunohistochemical staining, western blotting, and RT-qPCR analysis were performed to detect the EG-VEGF level in PC tissues and cells. Subsequently, two short hairpin RNA (shRNA) lentiviral expression vector, shPROK1-1/shPROK1-2, were transfected into PANC-1 and BxPC-3 PC cell lines. MTT assay was used to determine cell proliferation. Meanwhile, flow cytometry assay was conducted to measure cell cycle and cell apoptosis. The protein levels of PI3K/AKT/mTOR pathway-related genes were also determined by western blotting.
Results
EG-VEGF was aberrantly expressed in PC samples, as compared with paracancerous samples. Knockdown of PROK1 notably decreased the protein level of EG-VEGF, indicating a successful downregulation model of EG-VEGF. EG-VEGF silencing remarkably attenuated cell proliferation, while also induced G0/G1 arrest and magnified the extent of cell apoptosis. Further, EG-VEGF knockdown significantly inhibited PI3K/AKT/mTOR signaling pathway by downregulating p-PI3K, p-AKT, and p-mTOR levels.
Conclusion
This study identified the high-expression of EG-VEGF in pancreatic carcinoma tissues and cells, and demonstrated that EG-VEGF silencing inhibits the proliferation of PC cells and promotes apoptosis via regulating PI3K/AKT/mTOR pathway. Thus, EG-VEGF may become an essential target for the therapy of pancreatic cancer in the future.
Emerging data indicate that interferon‐induced transmembrane protein 1 (IFITM1) plays an important role in many cancers. However, it remains unclear whether IFITM1 is functionally indispensable in nonsmall cell lung cancer (NSCLC). Here, using NSCLC cell lines and patient‐derived samples, we show that IFITM1 is essentially required for the progression of NSCLC in vitro and in vivo. Specifically, IFITM1 depletion resulted in a significant reduction in sphere formation, migration, and invasion of NSCLC cells in vitro; these events were inversely correlated with the ectopic expression of IFITM1. In addition, tumor development was significantly impaired in the absence of IFITM1 in vivo. Mechanistically, epidermal growth factor receptor/sex‐determining region Y‐box 2 (EGFR/SOX2) signaling axis was compromised in the absence of IFITM1, and the ectopic expression of SOX2 partially rescued the defects caused by IFITM1 depletion. More importantly, using 226 patient‐derived samples, we demonstrate that a high level of IFITM1 expression is associated with a poor overall survival (OS) rate in adenocarcinoma but not in squamous cell carcinoma. Collectively, these data suggest that IFITM1 is a poor prognostic marker of adenocarcinoma and an attractive target to develop novel therapeutics for NSCLC.
Cryptotanshinone (CTT) is a natural product and a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miltiorrhizabunge. Notably, CTT has a variety of anti-cancer actions, including the activation of apoptosis, anti-proliferation, and reduction in angiogenesis. We further investigated the anti-cancer effects of CTT using MTS, LDH, and Annexin V assay, DAPI staining, cell cycle arrest, and Western blot analysis in NSCLC cell lines. NSCLC cells treated with CTT reduced cell growth through PI3K/Akt/GSK3β pathway inhibition, G0/G1 cell cycle arrest, and the activation of apoptosis. CTT induced an increase of caspase-3, caspase-9, poly-ADP-ribose polymerase (PARP), and Bax, as well as inhibition of Bcl-2, survivin, and cellular-inhibitor of apoptosis protein 1 and 2 (cIAP-1 and -2). It also induced G0/G1 phase cell cycle arrest by decreasing the expression of the cyclin A, cyclin D, cyclin E, Cdk 2, and Cdk 4. These results highlight anti-proliferation the latent of CTT as natural therapeutic agent for NSCLC. Therefore, we investigated the possibility of CTT as an anti-cancer agent by comparing with GF, which is a representative anti-cancer drug.
This research aimed to analyze the effect of IFITM1 on the radioresistance of oral neoplasm. IFITM1 emerged using multi‐group heat map from GSE9716 analysis of GEO database as the relevant radioresistance gene. IFITM1 was screened by TCGA database before its expression was analyzed. IFITM1 expression was quantified by qRT‐PCR and immunohistochemistry in 19 paired oral neoplasm cases. The effects of time and dose of radiation on IFITM1 expression level in CAL27 and TSCC1 cell lines was tested via qRT‐PCR. Oral neoplasm cells were transfected with siRNA after radiotherapy to disturb IFITM1 expression. After this the survival rates, cell apoptosis, caspase3 viability, expression and γ‐H2AX were detected using colony formation, flow cytometry, western blot and immunofluorescence respectively. Western blot was used for STAT1/2/3/p21 related protein and phosphorylation changes. Finally, an in vivo nude mice tumor model was established to verify the effect of IFITM1 on oral neoplasm cells radioresistance. Head and neck neoplasm radioresistance‐related gene IFITM1 was overexpressed using microarray. IFITM1 overexpression was verified not only in TCGA database but also in 19 paired cases of oral neoplasm tissues and cells. With increases of dose and time of radiation, the expression of IFITM1 was increased in CAL27 and TSCC1 cell lines. Further, si‐IFITM1 may restrain cell proliferation; DNA damage and cell apoptosis in oral neoplasm cell lines. Finally, pSTAT1/2/p21 was found up‐regulated while pSTAT3/p‐p21 was down‐regulated due to IFITM1 inhibition after radiotherapy. The evidence suggested IFITM1 in combination with radiotherapy can inhibit oral neoplasm cells.
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Introduction: Pancreatic cancer (PC) demonstrates very poor prognosis and its incidence continues to increase, despite developments in chemotherapy, radiotherapy, and targeted therapies. Surgical resection is currently the only curative approach for PC. The role of radiotherapy in adjuvant and locally advanced PC continues to be increasingly controversial. This review article aims to explore the current knowledge of pancreatic adenocarcinoma, focusing on diagnosis, treatment strategies, and the best supportive care.
Areas covered: The current literature on pancreatic adenocarcinoma treatment modalities has been summarized, with a focus on clinical trials and reviews. New treatment strategies and their impact on clinical practice have also been discussed.
Expert commentary: Despite many therapeutic developments, only modest improvements in survival rates have been achieved. There is an essential need to increase survival by developing more innovative treatment approaches for patients with PC.
Background
Cervical cancer is a major cause of death in women worldwide. Interferon-induced transmembrane protein 1 (IFITM1) is involved in antivirus defense, cell adhesion, and carcinogenesis in different tissues. However, the role of IFITM1 gene in cervical squamous cell cancer is unclear. Methods
To explore the role of IFITM1 in carcinogenesis of cervical cancer, we investigated the expression of IFITM1 gene in cervical squamous cell carcinoma. IFITM1 mRNA level was measured by real-time quantitative RT-PCR in cervical cancer tissues and their adjacent normal tissues. IFITM1 protein level was measured by immunohistochemistry. Methylation in the IFITM1 gene promoter was detected by methylation-specific PCR. We then transfected HeLa cells with IFITM1 expression vector or control vector. IFITM1 expression was examined; cell migration and invasion were analyzed by wound healing assay and matrigel-coated transwell migration assays, respectively. HeLa cell proliferation was measured by cell counting kit-8 assay and cell cycle analysis. Cell apoptosis was analyzed by Annexin V/propidium iodide double staining assay. ResultsThe difference in IFITM1 protein expression between samples from chronic cervicitis and cervical carcinoma was statistically significant (P < 0.01). Ki-67 and PCNA protein expression levels were significantly higher in cervical cancer tissues than in their corresponding cervicitis tissues (P < 0.05 and P < 0.001, respectively). IFITM1 mRNA level was significantly lower in cervical cancer tissues than in normal cervical tissues (P < 0.05). Methylation of the IFITM1 gene promoter was significantly higher in cervical cancer than in normal cervical tissues (P < 0.05). Transfection of the IFITM1 pcDNA3.1 construct decreased cell migration and invasion of HeLa cells, inhibited cell proliferation, and increased cell apoptosis. ConclusionIFITM1 gene expression may reduce the proliferation, migration, and invasion of cervical squamous cancer cells.
Interferon-induced transmembrane protein 1 (IFITM1) has been shown to be implicated in multiple cancers, yet little is known about biological significance of IFITM1 in colorectal cancer. Here, we show that IFITM1 is highly expressed in metastatic colorectal cancer cell lines as well as colorectal patient-derived tumor samples, and its expression is associated with a poor prognosis of the disease. Also, IFITM1 depletion resulted in a significant reduction in the mobility of cancer cell lines, whereas ectopic expression of IFITM1 promoted the migration of cancer cells. Epithelial-mesenchymal transition (EMT) signature was dysregulated by both loss and gain of function of IFITM1, which was partially reverted by Caveolin-1 (CAV1). Therefore, these results suggest that IFITM1 may be a prognostic marker and an attractive target to achieve better therapeutic outcomes in colorectal cancer.
Cancer is currently one of the most important public health problems in the world. Pancreatic cancer is a fatal disease with poor prognosis. As in most other countries, the health burden of pancreatic cancer in China is increasing, with annual mortality rates almost equal to incidence rates. The increasing trend of pancreatic cancer incidence is more significant in the rural areas than in the urban areas. Annual diagnoses and deaths of pancreatic cancer in China are now beyond the number of cases in the United States. GLOBOCAN 2012 estimates that cases in China account for 19.45% (65727/337872) of all newly diagnosed pancreatic cancer and 19.27% (63662/330391) of all deaths from pancreatic cancer worldwide. The population's growing socioeconomic status contributes to the rapid increase of China's proportional contribution to global rates. Here, we present an overview of control programs for pancreatic cancer in China focusing on prevention, early diagnosis and treatment. In addition, we describe key epidemiological, demographic, and socioeconomic differences between China and developed countries. Facts including no nationwide screening program for pancreatic cancer, delay in early detection resulting in a late stage at presentation, lack of awareness of pancreatic cancer in the Chinese population, and low investment compared with other cancer types by government have led to backwardness in China's pancreatic cancer diagnosis and treatment. Finally, we suggest measures to improve health outcomes of pancreatic cancer patients in China.
The prognosis for pancreatic cancer (PC) is very poor. The SnoN gene may have a role in cell proliferation and apoptosis in human cancer. However, the influence of SnoN on cell proliferation and apoptosis in human PC cells remains unknown.
SnoN expression was assessed in SW1990 PC cell lines using real-time polymerase chain reaction (PCR). A luciferase reporter assay was used to confirm the target associations. The effect of SnoN on cell proliferation in vitro was confirmed using Cell Counting Kit-8. Apoptosis was confirmed using flow cytometry. Gene and protein expression were examined using real time PCR and Western blotting, respectively.
SnoN siRNA significantly inhibited the growth of SW1990 cells by decreasing cell proliferation (P < 0.05) and increasing cell apoptosis (P < 0.05), compared with the blank group and the negative control group. The highest inhibition of cell proliferation appeared at 3 days post-transfection. Cell apoptosis more obvious at 48 h after transfection.
In summary, our results reveal that the RNAi-mediated downregulation of SnoN effectively inhibited the proliferation of PC cells. SnoN-siRNA also enhanced SW1990 PC cell apoptosis. These findings indicate that SnoN gene plays an important role in pancreatic cancer development, and might serve as a potential therapeutic target for pancreatic cancer. However, further in vivo studies are needed to clarify the influence of SnoN gene silencing by siRNA on pancreatic cancer therapy.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7609324661510147.
CD147, as a receptor for Cyclophilins, is a multifunctional transmembrane glycoprotein. In order to identify genes that are induced by activation of CD147, THP-1 cells were stimulated with Cyclophilin A and differentially expressed genes were detected using PCR-based analysis. Interferon-induced transmembrane 1 (IFITM1) was detected to be induced and it was confirmed by RT-PCR and Western blot analysis. CD147-induced expression of IFITM1 was blocked by inhibitors of ERK, PI3K, or NF-κB, but not by inhibitors of p38, JNK, or PKC. IFITM1 appears to mediate inflammatory activation of THP-1 cells since cross-linking of IFITM1 with specific monoclonal antibody against it induced the expression of proinflammatory mediators such as IL-8 and MMP-9. These data indicate that IFITM1 is one of the pro-inflammatory mediators that are induced by signaling initiated by the activation of CD147 in macrophages and activation of ERK, PI3K, and NF-κB is required for the expression of IFITM1.
Interferon-induced transmembrane protein 1 (IFITM1) has recently been identified as a new molecular marker in human colorectal cancer. However, its role in glioma carcinogenesis is not known. In this study, we demonstrated that suppression of IFITM1 expression significantly inhibited proliferation of glioma cells in a time-dependent manner. The growth inhibitory effect was mediated by cell cycle arrest. Furthermore, IFITM1 knockdown significantly inhibited migration and invasion of glioma cells, which could be attributed to decreased expression and enzymatic activity of matrix metalloproteinase 9. Taken together, these results suggest that IFITM1 is a potential therapeutic target for gliomas.
Bisphosphonates (BPs) are an emerging class of drugs mostly used in the palliative care of cancer patients. We investigated the in vitro activity of the most potent antiresorptive BP, zoledronic acid (ZOL), on the growth and survival of three human pancreatic cancer (PC) cell lines (BxPC-3, CFPAC-1 and PANC-1). Pancreatic cancer frequently has a dysregulated p21(ras) pathway and therefore appears to be a suitable target for BPs that interfere with the prenylation of small GTP-binding proteins such as p21(ras). We found that ZOL induces growth inhibition (IC(50):10-50 micro M) and apoptotic death of PC cells. The proapoptotic effect was correlated to cleavage/activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3. Moreover, we studied the p21(ras) signalling in cells exposed to ZOL and detected a reduction of p21(ras) and Raf-1 content and functional downregulation of the terminal enzyme ERK/MAPkinase and of the pKB/Akt survival pathway. Finally, we observed that ZOL induces significant cytoskeletal rearrangements. In conclusion, we demonstrated that ZOL induces growth inhibition and apoptosis on PC cells and interferes with growth and survival pathways downstream to p21(ras). These findings might be relevant for expanding application of BPs in cancer treatment.
The gene expression profile of pancreatic cancer is significantly different from that of normal pancreas. Differences in gene expression are detectable using microarrays, but microarrays have traditionally been applied to pancreatic cancer tissue obtained from surgical resection. We hypothesized that gene expression alterations indicative of pancreatic cancer can be detected by profiling the RNA of pancreatic juice.
We performed oligonucleotide microarray analysis on RNA isolated from pancreatic juice obtained endoscopically after secretin stimulation from six patients with pancreatic cancer and ten patients with nonneoplastic diseases of the pancreas or upper gastrointestinal tract. Extracted RNA was subjected to two rounds of linear RNA amplification, and then hybridized with U133A or X3P gene chips (Affymetrix).
Using the U133A or X3P chips, 37 and 133 gene fragments respectively, were identified as being at least 3-fold more abundant in the pancreatic juice of patients with pancreatic cancer compared to the noncancer controls (p<0.05, Mann-Whitney test). For example, pancreatic juice from patients with pancreatic cancer contained increased levels of IL8, IFITM1, fibrinogen, osteopontin, CXCR4, DAF and NNMT RNA, genes that have been previously reported as overexpressed in primary pancreatic cancers or pancreatic cancer cell lines relative to control tissues.
These results demonstrate that RNA analysis of pancreatic juice can reveal some of the same RNA alterations found in invasive pancreatic cancers. RNA analysis of pancreatic juice deserves further investigation to determine its utility as a tool for the evaluation of pancreatic lesions.
Prior laboratory prediction of individual drug response is of key importance in esophageal squamous cell carcinoma (ESCC), because of the extremely narrow therapeutic index of chemotherapy. However, very few critical markers have been validated to date for ESCC. We previously demonstrated that simultaneous performance of two different types of comprehensive gene expression analysis might provide a way to identify potent marker genes for drug sensitivity from the expression-sensitivity correlation analysis alone, but the screening method appeared not to be always effective. Therefore, we attempted to identify novel potent marker genes using a new statistical analysis of oligonucleotide microarray expression data, based on a two-dimensional mixed normal model, and selected 3 and 7 novel candidates for 5-fluorouracil (5-FU) and cis-platinum (CDDP), respectively. Interferon induced transmembrane protein 1 (IFITM1) gene alone, being suggested as a key gene of Wnt pathway, was commonly selected in both screening methods. The transfection analyses and siRNA-mediated knock-down experiments revealed that expression of IFITM1 closely related to cellular sensitivity to CDDP. Considering the fact that drug sensitivity is determined by multiple genes, we established the best linear model using quantified expression data of a set of all the selected marker genes including IFITM1, which converted the quantified expression data of ESCC cell lines into an IC50 value of each drug. In the same way, using the representative genes selected in vitro, we developed highly predictive formulae for disease-free survival (DFS) of the CDDP/5-FU combination after curative operation in esophageal cancer patients (R=0.917). A two-dimensional mixed normal model can be a powerful tool to identify novel drug-response determinants, and the IFITM1 gene selected by the statistical method a novel critical biomarker of CDDP response in ESCC.
Pancreatic cancer (PC) is a fatal disease; most patients are asymptomatic before the disease enters the advanced stage, but molecular mechanisms of early PC that can be exploited for diagnosis are not clear. Long noncoding RNAs (lncRNAs) play key roles in the progression of PC. In this study, we found that the expression of the lncRNA EPIC1 (Lnc-EPIC1) is high in PC and closely related to tumor size, TNM staging and lymph node metastasis status. Silencing Lnc-EPIC1 by siRNA targeting could significantly inhibit the cell growth and colony formation ability of PC cells and induced G1/S cell cycle arrest and apoptosis in PC cells. Lnc-EPIC1-specific siRNAs could downregulate the expression of cyclins and CDKs, such as CDC20, CDK4 and Cyclin A1. Knocking out YAP1 with the CRISPR/Cas-9 gene editing method recapitulated the effects of the Lnc-EPIC1-specific siRNAs on cell growth, colony formation ability and apoptosis in PC cells. In addition, the Lnc-EPIC1-specific siRNAs did not further inhibit cell growth or promote apoptosis in YAP1-knockout (YAP1-KO) cells. RNA immunoprecipitation (RIP) results showed that there was a direct interaction between Lnc-EPIC1 and YAP1. An Lnc-EPIC1-overexpressing lentiviral vector promoted the growth of PC cells. The results show that Lnc-EPIC1 interacts with YAP1 to promote the progression of PC.
Background and objectives:
Pancreatic cancer is one of the most lethal cancer types. Pancreatic cancer is highly malignant and characterized by rapid and uncontrolled growth. This study was designed to investigate the effect of baicalin on proliferation and apoptosis in pancreatic cancer cells.
Methods:
CCK-8 assay and Clone formation assay were performed to detect the effect of baicalin on proliferation in pancreatic cancer cells. Cell invasion and migration were all assessed with Wound healing assay and Transwell invasion assay. Flow Cytometry Analysis and DAPI staining were performed to detect the effect of baicalin on apoptosis in pancreatic cancer cells. Furthermore, proliferation-associated protein and apoptosis-related protein were detected to evaluate the cell proliferation and apoptosis levels. P-JNK protein, t-JNK protein, Foxo1 protein and BIM protein were examined by western blot to verify whether baicalin could regulate the proliferation and apoptosis via the JNK/Foxo1/BIM signaling pathway in pancreatic cancer cells.
Results:
The cell proliferation level was significantly decreased while the cell apoptosis level was significantly increased in pancreatic cancer SW1990 cells treated with baicalin. As the same, baicalin downregulated the ability of invasion and migration in pancreatic cancer SW1990 cells.
Conclusion:
Baicalin might inhibit cell proliferation and promote cell apoptosis via JNK/Foxo1/BIM signaling pathway in pancreatic cancer SW1990 cells.
Pancreatic cancer (PC) is one of the common malignant tumors in digestive tract with a high fatality rate. The oncogenic role of lysine-specific demethylase1 (LSD1/KDM1 A) has been well recognized in PC. While, the role of its homolog LSD2 (KDM1B) in regulating PC progression is poorly understood. In this study, we attempted to evaluate the functional role of KDM1B in PC cells. The expression of KDM1B was detected by immunohistochemistry and immunoblotting in PC tissues and cells. Lentivirus-mediated shRNA was applied to silence KDM1B in PANC-1 and SW1990 cells. Cell proliferation was measured by MTT and Celigo assay. Cell apoptosis was determined by both Caspase-Glo ® 3/7 assay and Flow cytometry. Intracellular signaling molecules were detected using a PathScan intracellular signaling array kit. In this study, we found KDM1B was highly expressed in PC tissues compared to paracancerous tissues. Moreover, elevated expression of KDM1B was detected in PC cell lines (BxPC-3, CFPAC-1, PANC-1 and SW1990) as compared with a normal human pancreatic duct epithelial cell line (HPDE6-C7). Further investigations revealed that KDM1B knockdown significantly inhibited PC cell proliferation. Furthermore, the apoptosis of PANC-1 and SW1990 cells was significantly increased after KDM1B knockdown. Notably, the activations of p-ERK1/2, p-Smad2, p-p53, cleaved PARP, cleaved Caspase-3, cleaved Caspase-7, p-eIF2a and Survivin were promoted by KDM1B knockdown, while IkBa was suppressed. Taken together, our findings provided new insights into the critical and multifaceted roles of KDM1B in the regulation of cell proliferation and apoptosis, and offered a potentially novel target in preventing the progression of PC.
Interferon induced transmembrane protein 1 (IFITM1) belongs to a family of interferon stimulated genes (ISGs) that is associated with tumor progression and DNA damage resistance, however, its role in endocrine resistance is not known. Here, we correlate IFITM1 expression with clinical stage and poor response to endocrine therapy in a tissue microarray consisting of 94 estrogen receptor (ER)-positive breast tumors. IFITM1 overexpression is confirmed in the AI-resistant MCF-7:5C cell line and not found in AI-sensitive MCF-7 cells. In this study, the orthotopic (mammary fat pad) and mouse mammary intraductal (MIND) models of breast cancer are used to assess tumor growth and invasion in vivo. Lentivirus-mediated shRNA knockdown of IFITM1 in AI-resistant MCF-7:5C cells diminished tumor growth and invasion and induced cell death, whereas, overexpression of IFITM1 in wild-type MCF-7 cells promoted estrogen-independent growth and enhanced their aggressive phenotype. Mechanistic studies indicated that loss of IFITM1 in MCF-7:5C cells markedly increased p21 transcription, expression and nuclear localization which was mediated by JAK/STAT activation. These findings suggest IFITM1 overexpression contributes to breast cancer progression and that targeting IFITM1 may be therapeutically beneficial to patients with endocrine-resistant disease.
Interferon-induced transmembrane protein 1 (IFITM1), a 17-kDa membrane protein, is largely known as a player in many cellular functions. Recently, there have been studies showing overexpression of IFITM1 in cancers and a positive correlation of IFITM1 overexpression with tumor progression. However, it is poorly understood what role IFITM1 plays in lung cancer. In this study, we presented evidence that IFITM1 was highly expressed in lung cancer tissues and cell lines. IFITM1 silencing inhibited lung cancer cell proliferation, migration and invasion in vitro . Furthermore, the in vivo experiments showed that IFITM1 silencing suppressed lung cancer cell growth and metastasis. Finally, we found that IFITM1 silencing decreased the protein levels of β-catenin, cyclin D1 and c-Myc in lung cancer cells. Taken together, our study suggested that IFITM1 might function as a tumor promoter during lung cancer development.
Interferon-induced transmembrane protein 1 (IFITM1) is one of the interferon-induced transmembrane protein family members. In this study, we reported that the elevated IFITM1 expression in human colorectal cancer (CRC) significantly correlated with CRC lymph node and distance metastasis as well as a more advanced clinical stage. Importantly, elevated IFITM1 expression is an independent prognostic factor for poor survival. To investigate the molecular mechanisms, we showed that over-expression of IFITM1 in CRC cells promoted, whereas knockdown of IFITM1 expression inhibited cell migration/invasion and tumorigenicity in vitro. Furthermore, we identified Caveolin-1 (CAV1) as a downstream target of IFITM1-induced cell invasion, as knockdown of CAV1 abrogated siIFITM1 mediated inhibition of cell invasion in CRC cells. In addition, in a CRC cohort of 229 patients, the expression of IFITM1 inversely correlated with the expression of CAV1. These results suggested that IFITM1 promotes the aggressiveness of CRC cells, and it is a potential prognostic marker and therapeutic target for CRC.
Copyright © 2015. Published by Elsevier Ireland Ltd.
A lack of reliable biomarkers for the early detection and risk of metastatic recurrences makes ovarian cancer the most lethal gynecological cancer. To understand the molecular mechanisms involved in ovarian cancer metastasis in vivo, we analyzed the transcriptional expression pattern in metastatic implants of human ovarian carcinoma xenografts in mice. The expression of 937 genes was significantly different, by at least 2-fold, in the xenografts compared with that in SK-OV-3 cells. We investigated the mechanisms that regulate the expression of one of the profoundly upregulated genes, interferon-induced transmembrane protein 1 (IFITM1), in the metastatic implants. Specific CpG sites within the IFITM1 promoter were hypomethylated in the metastatic implants relative to those in the wild-type SK-OV-3 cells. Treating wild-type SK-OV-3 cells with the demethylating agent 5-aza-2'-deoxycytidine enhanced IFITM1 expression in a dose-dependent manner, implying transcriptional regulation by promoter methylation. We also found that IFITM1 overexpression caused increased migration and invasiveness in SK-OV-3 cells. Our results demonstrate that IFITM1 could be a novel metastasis-promoting gene that enhances the metastatic phenotype in ovarian cancer via epigenetic transcriptional regulation. Our findings also suggest that the status of DNA methylation within the IFITM1 promoter region could be a biomarker indicating metastatic progression in ovarian cancer.
Background:
Pancreatic cancer is one of the most aggressive tumors with a dismal prognosis. The membrane cytoskeletal crosslinker Ezrin participates in several functions including cell proliferation, adhesion, motility and survival. There is increasing evidence that Ezrin is overexpressed in vast majority of malignant tumors and regulates tumor progression. However, its roles in pancreatic cancer remain elusive.
Methods:
Three pairs of specific Ezrin siRNAs were designed and synthetized and screened to determine the most efficient one for construction of a hairpin RNA plasmid targeting Ezrin. After transfection into the Panc-1 pancreatic cancer cell line, real-time quantitative PCR and Western blotting were performed to examine the expression of mRNA and protein. The MTT method was applied to examine the proliferation and the drug sensibility to Gemcitabine. Flow cytometry was used to assess the cycle and apoptosis, while capacity for invasion was determined with transwell chambers. Furthermore, we detected phosphorylated-Erk1/2 protein and phosphorylated-Akt protein by Western blotting.
Results:
Real-time quantitative PCR and Western blotting revealed that Ezrin expression was notably down-regulated at both mRNA and protein levels by RNA interference (P< 0.01). Proliferation was inhibited and drug resistance to gemcitabine was improved (P< 0.05). Flow cytometry showed that the proportion of cells in the G1/G0 phase increased (P< 0.01), and in G2/M and S phases decreased (P< 0.05), with no apparent differences in apoptosis (P> 0.05). The capacity for invasion was markedly reduced (P< 0.01). In addition, down-regulating Ezrin expression had no effect on phosphorylated-Akt protein (P>0.05), but could decrease the level of phosphorylated-Erk1/2 protein (P< 0.05).
Conclusions:
RNA interference of Ezrin could inhibit its expression in the pancreatic cancer cells line Panc-1, leading to a potent suppression of malignant behavior in vitro. Assessment of potential as a target for pancreatic cancer treatment is clearly warranted.
In an effort to identify novel genes related to the prognosis of gastric cancer, we performed gene expression profiling and found overexpressed levels of human interferon-induced transmembrane protein 1 (IFITM1). We validated the gastric cancer-specific up-regulation of IFITM1 and its association with cancer progression. We also studied its epigenetic regulation and tumorigenesis-related functions. Expression of IFITM1 was evaluated in various human gastric cancer cells and in 35 patient tumor tissues by quantitative RT-PCR and Western blot analyses. The results showed highly up-regulated IFITM1 in cancer cell lines and tissues. Furthermore, IHC studies were performed on 151 patient tissues, and a significant correlation was revealed between higher IFITM1 expression and Lauren's intestinal type (P = 0.007) and differentiated adenocarcinoma (P = 0.025). Quantitative studies of DNA methylation for 27 CpG sites in the regulatory region showed hypermethylation in cells expressing low levels of IFITM1. Methylation-dependent IFITM1 expression was confirmed further by in vitro demethylation using 5-aza-2'-deoxycytidine and luciferase assays. The functional analysis of IFITM1 by silencing of its expression with small-interfering RNA showed decreased migration and invasiveness of cancer cells, whereas its overexpression exhibited the opposite results. In this study, we demonstrated gastric cancer-specific overexpression of IFITM1 regulated by promoter methylation and the role of IFITM1 in cancer prognosis.
Interferon-induced transmembrane protein 1 (IFITM1) is an essential mediator of interferon-g-induced antiproliferation. Here, we reported the interaction between IFITM1 and caveolin-1 (CAV-1), and their inhibitory regulatory function on extracellular signal-regulated kinase (ERK). The immunofluorescence staining result showed that IFITM1 localized in caveolae of the plasma membrane and could interact with CAV-1. Deletion mutagenesis clearly revealed that the hydrophobic transmembrane domains were responsible for the interaction between IFITM1 and CAV-1. It has been reported that CAV-1 has inhibitory effect on the phosphorylation of ERK, and subsequently ERK-mediated transcription. Our study showed the interaction of IFITM1- and CAV-1-enhanced CAV-1's inhibitory effect on ERK activation, whereas the IFITM1 did not activate ERK directly. This inhibitory effect was further confirmed by knocking down the endogenous CAV-1 using RNA interference. These results revealed that the interaction between IFITM1 and CAV-1 could enhance the inhibitory effect of CAV-1 on ERK activation.
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine involved in antiproliferative and anti-virus responses, immune surveillance and tumor suppression. These biological responses to IFN-gamma are mainly mediated by the regulation of gene expression. It has been reported that growth-inhibitory role of IFN-gamma is dependent on activation of signal transducers and activators of transcription 1 (STAT1); however, the molecular basis downstream of STAT1 remains unclear. Here, we report that an IFN-gamma-induced gene, interferon-induced transmembrane protein 1 (IFITM1), plays a key role in the antiproliferative action of IFN-gamma. Overexpression of IFITM1 negatively regulated cell growth, whereas suppression of IFITM1 blocked the antiproliferative effect of IFN-gamma, accelerated the cell growth rate and conferred tumorigenicity to a non-malignant hepatocyte in nude mice. Further, IFITM1 could inhibit the activity of extracellular signal-regulated kinase, enhance the transcriptional activity of p53 and stabilize the p53 protein by inhibiting p53 phosphorylation on Thr55. Suppression of p53 reduced the growth-inhibitory capacity of both IFITM1 and IFN-gamma. Therefore, these findings indicated that the antiproliferative action of IFN-gamma requires the induction of IFITM1, and provided a crosstalk between two well-known signaling mediators, STAT1 and p53, both of which play critical roles in tumor suppression.
Selection of a novel drug-response predictor in esophageal cancer: a novel screening method using microarray and identification of IFITM1 as a potent marker gene of CDDP response
- Fumotos
- Shimokunit
- Tanimotok
Effect of baicalin on proliferation and apoptosis in pancreatic cancer cells
- Zhangj Huangq
- Pengj
Salvianolic acid B slows the progression of breast cancer cell growth via enhancement of apoptosis and reduction of oxidative stress, inflammation, and angiogenesis
- Abdelsayedr Kataryma
- Alhashima
Cryptotanshinone induces cell cycle arrest and apoptosis of NSCLC cells through the PI3K/Akt/GSK-3beta pathway
- Kangoh Kimsa
Long noncoding RNA EPIC1 interacts with YAP1 to regulate the cell cycle and promote the growth of pancreatic cancer cells
- Liup Xiap
- Fuq
Curcumin protects the pancreas from acute pancreatitis via the mitogen-activated protein kinase signaling pathway
- Wangy
- Buc
- Wuk
Interferon-induced transmembrane protein 1 (IFITM1) is required for the progression of colorectal cancer
- IN Sari
- YG Yang
- LT Phi
Interferon-induced transmembrane protein 1-mediated EGFR/SOX2 signaling axis is essential for progression of non-small cell lung cancer
- YG Yang
- YW Koh
- IN Sari