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Ring finger protein-128 (RNF128) overexpression promoted esophageal squamous cell carcinoma (ESCC) cell migration and invasion in vitro. RNF128-overexpression and control cells invaded through a matrigel-coated membrane (A) or migrated through a membrane (B). (C) RNF128, E-cadherin, N-cadherin, vimentin, and fibronectin expression in RNF128-overexpression and control cells were confirmed using Western blotting. Magnification for (A): ×40, magnification for (B): ×40.
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Background: The prognosis of esophageal squamous cell carcinoma (ESCC) is generally poor, and the identification of molecular markers related to the regulation of ESCC invasion and migration is important. Methods and Results: In this study, we report that ring finger protein-128 (RNF128) enhances the invasiveness and motility of ESCC cells by using...
Citations
... Experimental models using human ovarian cancer cells demonstrated that the activated ERK signaling pathway promoted the proliferation and migration of ovarian cancer ascites cells [28,79]. ERK activation can mediate tumor cell migratory activity by the up-regulation of genes involved in invasion, cell adhesion, extracellular matrix production, and degradation, and scaffold proteins that play essential roles in cell adhesion, transcription, and cytoskeletal organization [80][81][82] or matrix degradation [83,84]. Indeed, MEK inhibitors have been shown to block migration and invasion of many cancer cell types [85], including SK-OV-3 human ovarian carcinoma cells [86]. ...
Germ cell tumors (GCTs) are relatively rare tumors. However, they are the most diagnosed malignancies occurring in the testis among men aged between 15 and 40 years. Despite high aneuploidy and a paucity of somatic mutations, several genomic and transcriptomic assays have identified a few significantly mutated somatic genes, primarily KIT and K-RAS. The receptor Tyrosine Kinase (RTK) pathway and the downstream related Mitogen-Activated Protein Kinase (MAPK) cascades are crucial signal transduction pathways that preside over various cellular processes, including proliferation, differentiation, apoptosis, and responses to stressors. They are well described in solid malignancies, where many of the involved factors are used as prognostic molecular markers or targets for precision therapy. This narrative review focused, in the first part, on PGCs’ survival/proliferation and differentiation and on the genetic and epigenetic factors involved in the pathogenesis of testicular germ cell tumors (TGCTs) and, in the second part, on the most recent investigations about the KIT-RAS pathway in TGCTs and in other cancers, highlighting the efforts that are being made to identify targetable markers for precision medicine approaches.
... Experimental models using human ovarian cancer cells demonstrated that the activated ERK signaling pathway promoted the proliferation and migration of ovarian cancer ascites cells [28,79]. ERK activation can mediate tumor cell migratory activity by the up-regulation of genes involved in invasion, cell adhesion, extracellular matrix production and degradation, and scaffold proteins that play essential roles in cell adhesion, transcription, and cytoskeletal organization [80][81][82] or matrix degradation [83,84] . Indeed, MEK inhibitors have been shown to block migration and invasion of many cancer cell types [85], including SK-OV-3 human ovarian carcinoma cells [86]. ...
The receptor Tyrosine Kinase (RTK) pathway and the downstream related Mitogen Activated Protein Kinase (MAPK) cascades are crucial signal transduction pathways that preside over various cellular processes, including proliferation, differentiation, apoptosis, and responses to stressors. They are well described in solid malignancies, where many of the involved factors are used as prognostic molecular markers or targets for precision therapy. Germ cell tumors (GCTs) are relatively rare. However, they are the most diagnosed malignancies occurring in the testis (TGCT) among men aged between 15 and 40 years. Despite high aneuploidy and a paucity of somatic mutations, several genomic and transcriptomic assays have identified few significantly mutated somatic genes, primarily KIT and K-RAS, so affecting, at various levels, the KIT–RAS–RAF–MEK–ERK cascade. This review focuses on the most recent investigations about this signaling pathway in TGCTs concerning their development, natural history, response to standard chemotherapy protocols (i.e., cisplatin-based), and on the efforts being made to identify targetable markers for possible precision medicine approaches.
... Inhibitory role of β-sitosterol in glioma via EGFR/MAPK pathway activating the EGFR/MAPK signaling pathway and promoting the occurrence and metastasis of hepatocellular carcinoma [48]. RNF128 regulates the expression of MMP-2 by activating the EGFR/MAPK signaling pathway, thereby promoting the invasion and metastasis of esophageal squamous cell carcinoma [49]. The study found that β-sitosterol treatment significantly inhibited the EGFR/MAPK signaling pathway, indicating that the EGFR/MAPK signaling pathway was involved in β-sitosterol-mediated proliferation, cell cycle arrest, apoptosis and migration in U87 cells. ...
Glioma is characterized by rapid cell proliferation, aggressive invasion, altered apoptosis and a poor prognosis. β-Sitosterol, a kind of phytosterol, has been shown to possess anticancer activities. Our current study aims to investigate the effects of β-sitosterol on gliomas and reveal the underlying mechanisms. Our results show that β-sitosterol effectively inhibits the growth of U87 cells by inhibiting proliferation and inducing G2/M phase arrest and apoptosis. In addition, β-sitosterol inhibits migration by downregulating markers of epithelial-mesenchymal transition (EMT). Mechanistically, network pharmacology and transcriptomics approaches illustrate that the EGFR/MAPK signaling pathway may be responsible for the inhibitory effect of β-sitosterol on glioma. Afterward, the results show that β-sitosterol effectively suppresses the EGFR/MAPK signaling pathway. Moreover, β-sitosterol significantly inhibits tumor growth in a U87 xenograft nude mouse model. β-Sitosterol inhibits U87 cell proliferation and migration and induces apoptosis and cell cycle arrest in U87 cells by blocking the EGFR/MAPK signaling pathway. These results suggest that β-sitosterol may be a promising therapeutic agent for the treatment of glioma.
... 27 Meanwhile, RNF128 could promote EGFR phosphorylation by interacting with p53, thereby regulating MAPK/ MMP-2 signalling pathway to the invasion and metastasis of oesophageal squamous cell carcinoma. 28 C-CBL, also as a RING finger E3 ubiquitin ligase, could ubiquitinate EGFR and promote its internalization and degradation. 29 RNF12, as a member of the ring finger protein family, has been reported to be dysregulated in many malignancies. ...
Liver cancer is one of the most common solid tumours, and ranks as the third leading cause of cancer-associated mortality around the world. This study has linked RNF12 to the pathogenesis of liver cancer. Based on the analysis of patient samples and database data, high RNF12 expression was found in liver cancer, in correlation with worse clinicopathological features and a poor prognosis. Meantime, RNF12 could promote the progression of liver cancer in vitro and in vivo. Mechanistically, RNF12 could interact with EGFR and decrease the internalization of EGFR to activate EGF/EGFR signalling. In addition, PI3K-AKT signalling takes part in the regulation of liver cancer cell proliferation and migration of RNF12. And AKT inhibitor MK2206 could reverse RNF12-mediated cellular proliferation and migration in liver cancer. The possibility of the physical interaction between RNF12 and EGFR might lay a foundation to develop intervention strategies for liver cancer prevention and therapy.
... 11 Moreover, RNF128 interacts with p53 and activates the EGFR/MAPK/ MMP-2 pathway, promoting the invasiveness and migratory ability of esophageal squamous cell carcinoma. 12 In melanoma, however, RNF128 regulates Wnt/β-catenin signaling to suppress epithelial-mesenchymal transformation (EMT) and stemness through a mechanism involving CD44 ubiquitination. 13 The downregulation of RNF128 expression is associated with poor prognosis in the upper urinary tract and bladder cancers. ...
Objectives:
Molecular-level research has linked RING finger (RNF) protein family members to carcinogenesis and tumor progression. Among them, RNF128 is related to tumor progression, but reports on its association with lung cancer are few. This study aimed to clarify the unknown association between RNF128 expression and clinical outcomes in patients with lung adenocarcinoma.
Methods:
Clinical data of 545 patients with therapy-naïve lung adenocarcinoma who underwent lobectomy with systematic lymph node dissection between 1999 and 2016 were retrospectively reviewed. Histological and immunohistochemical analyses were conducted to evaluate the relationship between RNF128 expression and prognosis.
Results:
Among adenocarcinoma histologic types, acinar, micropapillary, and solid tumors did not express RNF128 compared with other histologic types (p < 0.001). Patients with high RNF128 expression exhibited fewer clusters of differentiated (CD) 68+ tumor-associated macrophages (TAMs) and CD163+ TAMs. Multivariate analysis of relapse-free survival (RFS) and overall survival (OS) revealed that the lack of RNF128 expression was an independent prognostic factor for poor RFS (hazard ratio [HR] 1.60, p = 0.029) and OS (HR 1.83, p = 0.041), suggesting that RNF128 expression is a favorable prognostic factor.
Conclusion:
RNF128 expression may be an independent predictor of favorable outcomes in Japanese patients with untreated lung adenocarcinoma who undergo surgical resection. Further elucidation of the role of TAM-related E3 ubiquitin ligase in immune function may facilitate the development of effective immunomodulatory therapies for lung adenocarcinoma.
... MEK and ERK1/2 are involved in cell survival, proliferation, and differentiation depending on their phosphorylated targets [86]. Activation of ERK/ MAPK signaling pathway could promote tumor cell invasion and metastasis through upregulation of MMP expression [87]. JNK and p38 signaling pathways are activated by pro-inflammatory cytokines, such as TNF-α and IL-1β, or are involved in response to cellular stress [88]. ...
Colorectal cancer (CRC) is a disease with complex pathogenesis, it is prone to metastasis, and its development involves abnormalities in multiple signaling pathways. Surgery, chemotherapy, radiotherapy, target therapy, and immunotherapy remain the main treatments for CRC, but improvement in the overall survival rate and quality of life is urgently needed. Traditional Chinese medicine (TCM) has a long history of preventing and treating CRC. It could affect CRC cell proliferation, apoptosis, cell cycle, migration, invasion, autophagy, epithelial–mesenchymal transition, angiogenesis, and chemoresistance by regulating multiple signaling pathways, such as PI3K/Akt, NF-κB, MAPK, Wnt/β-catenin, epidermal growth factor receptors, p53, TGF-β, mTOR, Hedgehog, and immunomodulatory signaling pathways. In this paper, the main signaling pathways and potential targets of TCM and its active ingredients in the treatment of CRC were systematically summarized, providing a theoretical basis for treating CRC with TCM and new ideas for further exploring the pathogenesis of CRC and developing new anti-CRC drugs.
... Recently, aberrant expression of RNF128 has been identified in several tumors, for example, RNF128 regulates tumorigenesis by interacting with p53 and regulating its degradation (9). In esophageal squamous cell carcinoma and hepatocellular carcinoma, RNF128 promotes malignant tumor behavior through activation of the EGFR/ERK signaling pathway (10,11). However, in melanoma, upper gastrointestinal tract and bladder urothelial carcinoma, RNF128 is downregulated and associated with a poor prognosis (12,13). ...
... Downregulation of RNF128 is also associated with a poor prognosis in patients with urothelial carcinoma of the upper tract and urinary bladder (13). In hepatocellular carcinoma and esophageal carcinoma, high expression of RNF128 promotes malignant behaviors in cancer cells through activation of the EGFR/ ERK signaling pathway (10,11). ...
Background
Colorectal cancer is a common malignancy of the gastrointestinal tract, and its incidence and mortality rates have increased in recent years. RNF128 is an E3 ubiquitin ligase that plays an important role as a suppressor gene or oncogene in various cancers, but its mechanism in colorectal cancer is not yet clear. The aim of this study was to investigate the role and mechanism of RNF128 in colorectal cancer.
Methods
The expression of RNF128 in colorectal cancer tissues was assessed by immunohistochemistry and western blotting. The proliferation ability of colorectal cancer cells was measured by colony formation assay and CCK-8 assay, the migration and invasion ability of colorectal cancer cells was measured by wound healing assay and transwell assay, and the protein expression levels of the Hippo signaling pathway and its target gene were examined by western blotting. Immunoprecipitation was used to assess the interaction of RNF128 with MST. In vivo, a xenograft tumor model was used to detect the effect of RNF128 on tumor growth.
Results
At the tissue level, the expression level of RNF128 was significantly higher in colorectal cancer tissues than in adjacent normal tissues. In LoVo cells and HCT116 cells, the proliferation, migration and invasion abilities were significantly reduced with RNF128 knockdown. At the protein level, knockdown of RNF128 resulted in significant activation of the Hippo signaling pathway. In vivo experiments, the volume and weight of xenograft tumors in nude mice were significantly decreased compared with those in the normal control group with RNF128 knockdown.
Conclusion
RNF128 promotes the malignant behaviors of colorectal cancer cells by inhibiting the Hippo signaling pathway, which may provide a new target for colorectal cancer prevention and treatment.
... Any alteration of mucin, which is necessary for the preservation of the mucosal barrier of the gut, may breach its integrity [41]. Clostridiales, butyrate-producing bacteria, was found in low concentrations in obese patients, T2D patients, and GDM in the second trimester [24, [42][43][44][45]. The Enterobacteriaceae family was correlated with HbA1C levels in previous studies, being more abundant in the second trimester in GDM women and in type 2 diabetic patients compared to control groups [24, 46,47]. ...
Gestational diabetes mellitus (GDM), one of the most common endocrine pathologies during pregnancy, is defined as any degree of glucose intolerance with onset or first discovery in the perinatal period. Physiological changes that occur in pregnant women can lead to inflammation, which promotes insulin resistance. In the general context of worldwide increasing obesity in young females of reproductive age, GDM follows the same ascending trend. Changes in the intestinal microbiome play a decisive role in obesity and the development of insulin resistance and chronic inflammation, especially in patients with type 2 diabetes mellitus (T2D). To date, various studies have also associated intestinal dysbiosis with metabolic changes in women with GDM. Although host metabolism in women with GDM has not been fully elucidated, it is of particular importance to analyze the available data and to discuss the actual knowledge regarding microbiome changes with potential impact on the health of pregnant women and newborns. We analyzed peer-reviewed journal articles available in online databases in order to summarize the most recent findings regarding how variations in diet and metabolic status of GDM patients can contribute to alteration of the gut microbiome, in the same way that changes of the gut microbiota can lead to GDM. The most frequently observed alteration in the microbiome of patients with GDM was either an increase of the Firmicutes phylum, respectively, or a decrease of the Bacteroidetes and Actinobacteria phyla. Gut dysbiosis was still present postpartum and can impact the development of the newborn, as shown in several studies. In the evolution of GDM, probiotic supplementation and regular physical activity have the strongest evidence of proper blood glucose control, favoring fetal development and a healthy outcome for the postpartum period. The current review aims to summarize and discuss the most recent findings regarding the correlation between GDM and dysbiosis, and current and future methods for prevention and treatment (lifestyle changes, pre- and probiotics administration). To conclude, by highlighting the role of the gut microbiota, one can change perspectives about the development and progression of GDM and open up new avenues for the development of innovative therapeutic targets in this disease.
... Moreover, we found that expression of TIA1 had a strong correlation with RNF128 AP (r = − 0.56, P < 0.001, Fig. 11D). It was reported that RNF128 functions as an E3 ligase and involved in promoting invasion and metastasis in several types of cancer [30,31]. Hence, it might be reasonable that TIA1 could affect survival via the regulation of aberrant alternative splicing of RNF128 pre-mRNA. ...
Background
Bladder cancer is one of the most lethal malignancy in urological system, and 20–25% of bladder cancer patients are muscle invasive with unfavorable prognosis. However, the role of alternative splicing (AS) in muscle-invasive bladder cancer (MIBC) remains to be elucidated.
Methods
Percent spliced in (PSI) data obtained from the Cancer Genome Atlas (TCGA) SpliceSeq database ( n = 394) were utilized to evaluate the AS events in MIBC. Prognosis-associated AS events were screened out by univariate Cox regression. LASSO Cox regression was used to identify reliable prognostic patterns in a training set and further validated in a test set. Splicing regulatory networks were constructed by correlations between PSI of AS events and RNA expression of splicing factors.
Results
As a result, a total of 2589 prognosis-related AS events in MIBC were identified. Pathways of spliceosomal complex ( FDR = 0.017), DNA-directed RNA polymerase II, core complex ( FDR = 0.032), and base excision repair ( FDR = 0.038) were observed to be significantly enriched. Additionally, we noticed that most of the prognosis-related AS events were favorable factors. According to the LASSO and multivariate Cox regression analyses, 15-AS-based signature was established with the area under curve (AUC) of 0.709, 0.823, and 0.857 at 1-, 3-, and 5- years, respectively. The MIBC patients were further divided into high- and low-risk groups based on median risk sores. Interestingly, we observed that the prevalence of FGFR3 with mutations and focal amplification was significantly higher in low-risk group. Functional and immune infiltration analysis suggested potential signaling pathways and distinct immune states between these two groups. Moreover, splicing correlation network displayed a regulatory mode of prognostic splicing factors (SF) in MIBC patients.
Conclusions
This study not only provided novel insights into deciphering the possible mechanism of tumorgenesis and pathogenesis but also help refine risk stratification systems and potential treatment of decision-making for MIBC.
... In the nucleus, proto-oncogenes including c-FOS, c-JUN, ETS domain-containing protein (ELK1), c-MYC, and cyclic AMP-dependent transcription factor (ATF2) are all phosphorylated in an ERK1/2-dependent manner [126]. The activation of the ERK/MAPK signaling pathway can promote tumor invasion and metastasis by upregulating MMP expression, whereas the inhibition of this signaling can impede the aforementioned processes [164,165]. It was also discovered that mesothelin regulates the expression of MMP7 through the MAPK/ERK signal transduction pathway, as well as the ERK1/2, AKT, and JNK-mediated pathways, contributing to the invasiveness of ovarian cancer cells [166]. ...
... Moreover, RAS-associated protein RAP1A was identified as a significant promoter of ovarian cancer cell metastasis via activation of ERK and P38 signaling and the induction of EMT through enhanced expression of SLUG, ZEB1, vimentin, fibronectin, and MMP9 [167]. pathway can promote tumor invasion and metastasis by upregulating MMP expression, whereas the inhibition of this signaling can impede the aforementioned processes [164,165]. It was also discovered that mesothelin regulates the expression of MMP7 through the MAPK/ERK signal transduction pathway, as well as the ERK1/2, AKT, and JNKmediated pathways, contributing to the invasiveness of ovarian cancer cells [166]. ...
Cancer is a leading cause of death worldwide. In many cases, the treatment of the disease is limited due to the metastasis of cells to distant locations of the body through the blood and lymphatic drainage. Most of the anticancer therapeutic options focus mainly on the inhibition of tumor cell growth or the induction of cell death, and do not consider the molecular basis of metastasis. The aim of this work is to provide a comprehensive review focusing on cancer metastasis and the mitogen-activated protein kinase (MAPK) pathway (ERK/JNK/P38 signaling) as a crucial modulator of this process.
