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JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in ovarian cancer patients. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this...
Citations
... Due to these reasons, JAK1 alone, its upstream regulators such as miR-494-5p, and/or its downstream target(s) are good candidates for new therapy options. Consequently, some drugs that at least target the JAK/STAT pathway are in clinical trials, exploring these possibilities in diverse cancer types, including CRC [35,74]. Particularly the JAK1/2 inhibitor ruxolitinib was shown to decrease the JAK1/2-STAT1-Mcl-1 protein level and effectively suppressed CRC cell proliferation in vitro and in vivo [75]. ...
Simple Summary
MicroRNA (miR) 494-5p has been associated with cancer progression, but molecules mediating this are not well understood. Here, we show that the 3’UTR of JAK1 is physically targeted, and JAK1 is downregulated in expression by miR-494-5p in colorectal cancer (CRC). Additionally, CRC cell proliferation, spontaneous and IL-4-induced invasion, and migration were significantly reduced by this miR, as well as IL-4-induced phosphorylation of JAK1, STAT6, and AKT. High JAK1 expression significantly correlated with reduced patient survival. Together, our findings suggest JAK1 as a novel target of miR-494-5p, with its translational repression contributing to CRC progression and the initial steps of metastasis.
Abstract
MiR-494-5p expression has been suggested to be associated with colorectal cancer (CRC) and its metastases in our previous studies. However, functional investigations on the molecule-mediating actions of this miR in CRC are lacking. In silico analysis in the present study revealed a putative binding sequence within the 3′UTR of JAK1. Overexpression of miR-494-5p in cultured CRC significantly reduced the luciferase activity of a reporter plasmid containing the wild-type JAK1-3′UTR, which was abolished by seed sequence mutation. Furthermore, the overexpression of miR-494-5p in CRC cell lines led to a significant reduction in JAK1 expression, proliferation, in vitro migration, and invasion. These effects were abolished by co-transfection with a specific double-stranded RNA that inhibits endogenous miR-494-5p. Moreover, IL-4-induced migration, invasion, and phosphorylation of JAK1, STAT6, and AKT proteins were reduced after an overexpression of this miR, suggesting that this miR affects one of the most essential pathways in CRC. A Kaplan–Meier plotter analysis revealed that patients with high JAK1 expression show reduced survival. Together, these data suggest that miR-494-5p physically inhibits the expression of JAK1 at the translational level as well as in migration and invasion, supporting the hypothesis of miR-494-5p as an early tumor suppressor and inhibitor of early steps of metastasis in CRC.
... There is growing evidence that senescence and the SASP in ovarian cancer can promote dissemination (Veenstra, Bittencourt, and Aird 2022). Studies have shown that cytokines IL-6 and IL-8 are both known to enhance ovarian cancer dissemination through JAK/STAT3 signaling and through induction of anoikis resistance (Wen et al. 2014;Mehner et al. 2020;Lane et al. 2011), though these studies were independent of senescence induction. Senescence has been explored in the context of cancer and has been shown to lead to a number of deleterious cancer phenotypes, specifically metastasis (Acosta and Gil 2012;Coppe et al. 2010;Rodier and Goldstein 2008;Krtolica et al. 2001;Parrinello et al. 2005;Tsai et al. 2005), though often studied in the context of direct remodeling of the extracellular matrix through the increased expression of matrix metalloproteinases (MMPs) in the SASP (Parrinello et al. 2005;Liu and Hornsby 2007;Tsai et al. 2005;Camphausen et al. 2001;Qian et al. 2002). ...
High grade serous ovarian cancer (HGSOC) is the most lethal gynecological cancer. Platinum-based therapies such as cisplatin are standard-of-care for HGSOC patients; however, the majority of HGSOCs initially treated with cisplatin will recur with widespread disseminated disease. Cisplatin induces cellular senescence, a stable cell cycle arrest. Although they are non-proliferative, senescent cells secrete a complex mix of cytokines and small molecules, named the senescence associated secretory phenotype (SASP), that have been shown to have pro-tumorigenic effects. To investigate how the SASP contributes to HGSOC progression, we used conditioned media from cisplatin therapy-induced senescent cells to culture naive HGSOC spheroids. We report that while the SASP does not affect spheroid formation, the adhesion of cells within spheroids is altered, leading to cell detachment from spheroids. Interestingly, our data indicate that this occurs in an MMP-independent manner. Analysis of RNA-Seq samples indicates many adhesion-related genes and adhesion factors are transcriptionally downregulated by the SASP, particularly fibronectin and integrins, which was validated by immunofluorescence in spheroids. These data reveal that senescent cells contribute to a transcriptional program in nearby cancer cells in a paracrine fashion that decreases their adhesion, which may contribute to tumor dissemination.
... IL-6 was found to activate the JAK/STAT3 pathway and could promote tumor metastasis in ovarian cancer by enhancing the proliferation, migration, and invasion of tumor cells [76]. Targeted inhibition of JAK/STAT3 pathway can lead to reversal of immunosuppression and activation of immune cells to attack the tumor, resulting in decreased tumor growth and enhanced anti-tumor immune response [77,78]. ...
Background
Mitophagy is a process of selectively degrading damaged mitochondria, which has been found to be related to immunity, tumorigenesis, tumor progression, and metastasis. However, the role of mitophagy-related genes (MRGs) in the tumor microenvironment (TME) of ovarian cancer (OV) remains largely unexplored.
Methods
We analyzed the expression, prognosis, and genetic alterations of 29 MRGs in 480 OV samples. Unsupervised clustering was used to classify OV into two subtypes (clusters A and B) based on MRG changes. We compared the clinical features, differential expressed genes (DEGs), pathways, and immune cell infiltration between the two clusters. We constructed a mitophagy scoring system (MRG_score) based on the DEGs and validated its ability to predict overall survival of OV patients.
Results
We found that patients with high MRG_scores had better survival status and increased infiltration by immune cells. Further analysis showed that these patients may be more sensitive to immune checkpoint inhibitor (ICI) treatment. Additionally, the MRG_score significantly correlated with the sensitivity of chemotherapeutic drugs and targeted inhibitors.
Conclusion
Our comprehensive analysis of MRGs in the TME, clinical features, and patient prognosis revealed that the MRG_score is a potentially effective prognostic biomarker and predictor of treatment. This study provides new insights into the role of MRGs in OV and identifies patients who may benefit from ICI treatment, chemotherapy, or targeted treatment.
... Additionally, immune-based therapies, including chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers (BiTEs), are being evaluated for their potential to harness the immune system in targeting leukemic cells [7]. Furthermore, agents targeting key signaling pathways implicated in Ph-Like ALL, such as the JAK-STAT pathway, are showing promise in preclinical studies [8].These emerging therapies represent a significant stride towards more effective and targeted treatment options for patients. ...
Acute lymphoblastic leukemia (ALL) is considered as the most common pediatric malignancy with 80% of frequency in children between 1 and 10 years old. With the evolution of science, improved diagnosis and adapted treatment, all survival rates increased to a possibility of 80%. Philadelphia chromosome like acute lymphoblastic leukemia (Ph-Like ALL) is a recent genetic discovery characterized by a gene expression profile and high frequency of IKZF1 gene alteration similar to that of BCR-ABL1 positive ALL with a poor outcome. We can identify it in 10% to 15% in children, 20% in adolescents (between 16-20 years old) and young adults. It has been reported that ALL Ph like is known with a high frequency in relapse. Yet, adapted treatment with ITK can improve prognosis of patients with this abnormality. The standard diagnostic BAll panel includes testing for abnormalities using cytogenetic techniques such as karyotype and FISH completed by molecular techniques if needed to explore cryptic abnormalities. Before testing the Philadelphia like BALL , some abnormalities need to be excluded such as hyperdiploidy, BCR-ABL1, ETV6-RUNX1, MLL. 6 subtypes of ALL Ph like were identified so far.
... Abnormally constitutive activation of the JAK/STAT pathway is associated with tumor progression and a poor prognosis in OC [208]. JAK/STAT pathway mediates tumor progression through the induction of numerous proteins and cytokines attributed to cell proliferation, stemness, and evasion from antitumor immunity [209]. ...
Advanced and recurrent gynecological cancers lack effective treatment and have poor prognosis. Besides, there is urgent need for conservative treatment for fertility protection of young patients. Therefore, continued efforts are needed to further define underlying therapeutic targets and explore novel targeted strategies. Considerable advancements have been made with new insights into molecular mechanisms on cancer progression and breakthroughs in novel treatment strategies. Herein, we review the research that holds unique novelty and potential translational power to alter the current landscape of gynecological cancers and improve effective treatments. We outline the advent of promising therapies with their targeted biomolecules, including hormone receptor-targeted agents, inhibitors targeting epigenetic regulators, antiangiogenic agents, inhibitors of abnormal signaling pathways, poly (ADP-ribose) polymerase (PARP) inhibitors, agents targeting immune-suppressive regulators, and repurposed existing drugs. We particularly highlight clinical evidence and trace the ongoing clinical trials to investigate the translational value. Taken together, we conduct a thorough review on emerging agents for gynecological cancer treatment and further discuss their potential challenges and future opportunities.
... AKT2 is one of the components of the PI3K-Akt signaling and, with the JAK/STAT3 signaling pathway, has a critical role in promoting malignant transformation in human tumors [53]. The JAK/STAT3 pathway is also activated and associated with tumor progression and poor prognosis in patients with ovarian cancer [54], and is a potential target for new therapeutic agents [55]. Critically ill patients with SARS-CoV2 viral infections also seem to hyperactivate the JAK1/2-STAT1 signaling pathway [56]. ...
... However, to understand the mechanism of interaction of bacteria with the underlying epithelium and the signaling pathways that may be affected, such as JAK/STAT3 or PI3K-AKT/mTOR, functional analyses are needed. Furthermore, functional analyses are better suited to assess whether any changes in the microbiome could help in selecting targeted therapies against the JAK1/STAT3 signaling pathway such as JAK inhibitors [54], or mTOR inhibitors to target the PI3K-AKT/mTOR pathway [55]. ...
Simple Summary
Bacteria are responsible for a wide range of human diseases including cancer. In our study we identified changes in the microbial communities of the female upper genital tract correlated with genomic variation in genes seen in gynecological cancers, endometrial and ovarian. This supports our hypothesis that differences in bacterial communities in the upper genital tract epithelium may lead to selection of specific genomic variation at the cellular level of these tissues that may predispose to their malignant transformation. Pathway analyses including correlated genes with changing microbiome may help understand how changing bacterial landscapes could lead to these cancers.
Abstract
There are strong correlations between the microbiome and human disease, including cancer. However, very little is known about potential mechanisms associated with malignant transformation in microbiome-associated gynecological cancer, except for HPV-induced cervical cancer. Our hypothesis is that differences in bacterial communities in upper genital tract epithelium may lead to selection of specific genomic variation at the cellular level of these tissues that may predispose to their malignant transformation. We first assessed differences in the taxonomic composition of microbial communities and genomic variation between gynecologic cancers and normal samples. Then, we performed a correlation analysis to assess whether differences in microbial communities selected for specific single nucleotide variation (SNV) between normal and gynecological cancers. We validated these results in independent datasets. This is a retrospective nested case-control study that used clinical and genomic information to perform all analyses. Our present study confirms a changing landscape in microbial communities as we progress into the upper genital tract, with more diversity in lower levels of the tract. Some of the different genomic variations between cancer and controls strongly correlated with the changing microbial communities. Pathway analyses including these correlated genes may help understand the basis for how changing bacterial landscapes may lead to these cancers. However, one of the most important implications of our findings is the possibility of cancer prevention in women at risk by detecting altered bacterial communities in the upper genital tract epithelium.
... Over 50% constitutive activation of STAT3 is seen in lung and breast cancers and 95% of activation in neck and head cancers (Darnell, 2005). In in vivo, JAK/-STAT signaling pathway inhibition causes a significant decrease in peritoneal dissemination and inhibits tumor growth in ovarian cancer (Wen et al., 2014). Interaction of IFNγ cytokine with suppressor of cytokine signaling (SOCS) acts as a significant inhibitor in JAK/STAT pathway (Bachmann et al., 2011;Lindemann et al., 2011). ...
Cancer is characterized by alterations that cause the over-proliferation of cells and hyperactivation of signaling pathways. Alterations of signaling molecules dysregulate physiological functions like cell growth, proliferation, metastasis, and cell death. Hence, the potential anticancer compounds primarily target signaling networks for therapeutic interventions in cancer. In the past few years, cancer therapy directed its focus on bioactive compounds that originated from marine sources considering their diverse and untapped nature. These Marine Bioactive Compounds (MBCs) are broadly classified into distinct categories such as alkaloids, carbohydrates, fatty acids, peptides, phenols, quinones, terpenes, and saponins. Bioactive compounds from each class initiate cell death via different signaling pathways. The primary objective of this review is to provide comprehensive information about the pathways that are predominantly followed by every class of MBCs by integrating data from several marine anticancer research. Here, we studied the signaling networks followed by each class of MBCs to inhibit various cancer types. As a result, we concluded that PI3K/AKT, ROS, and p53 are the three major signaling pathways targeted by the MBCs to induce apoptosis in cancer cells and these pathways are predominantly observed in classes like carbohydrates, peptides, and terpenes. Hence it is concluded that future anticancer research can be primarily focused on the MBCs derived from the scrutinized classes that adhere to pathways like PI3K/AKT, ROS, and p53 to achieve par excellence results.
... Janus kinase 1 (JAK1), responsible for phosphorylating STAT3, is another critical member of the JAK1/ STAT3 signaling pathway. JAK1/STAT3 pathway is activated in many malignant tumors and plays a critical role in promoting cancer initiation [23,24]. A previous study showed that JAK1/STAT3 pathway was activated in colorectal cancer cells, accompanied by the increased phosphorylation level of JAK1 and STAT3 [25]. ...
Objective:
We attempted to clarify the effect of lncRNA MSC-AS1 on carcinogenic and development of nasopharyngeal carcinoma (NPC) and the related mechanisms.
Methods:
The levels of MSC-AS1 and miR-429 were estimated in NPC tissues and cells using qRT-PCR. Correlation analysis, dual-luciferase report, and RNA pull down assay assessed the action association of MSC-AS1 and miR-429. MTT, colony formation, cell wound scratch, and transwell assays were used to assess the proliferation, invasion, and migration of C666-1 cells. Metastasis-related protein expressions and activation of the JAK1/STAT3 pathway were confirmed by western blot and immunohistochemistry.
Results:
The expression of MSC-AS1 presented significant upregulation, and miR-429 expression was markedly downregulated in NPC tissues and cells. The level of MSC-AS1 had negative relation to the miR-429 level. Knockdown of MSC-AS1 suppressed the proliferation, invasion, and migration of C666-1 cells. On the contrary, overexpressing of MSC-AS1 exerts the opposite effects on C666-1 cell growth and migration. miR-429 was determined as functional downstream of MSC-AS1. The suppressive function of MSC-AS1 knockdown was predominately abolished by the miR-429 inhibitor. miR-429 was an antitumor gene inhibiting NPC growth and metastasis through JAK1/STAT3 pathway. In C666-1 cells, the elevated cell growth and migration induced by the miR-429 inhibitor were significantly reversed by si-JAK1 transfection.
Conclusions:
High expression of MSC-AS1 exerted a carcinogenic effect on NPC cell growth and metastasis by inhibiting miR-429 and activating the JAK1/STAT3 pathway.
... Many factors are involved in metastasis, including cytokines and changes in gene expression and the tumor microenvironment. More than 80% of ovarian cancer patients die from metastasis [3]. ...
Although ovarian cancer has long been recognized as a serious threat to women's health worldwide, major questions remain about effective treatment. Plants are considered as a huge resource for searching anti-cancer compounds. In previous studies, the plant-derived agent kaempferol-3-O-rutinoside (KR) was shown to have anti-tumor effects on lung cancer, colon cancer, and malignant melanoma. However, its mechanism of action is not well understood. Here, we demonstrated that KR inhibited expression of integrin beta 1 and suppressed the motility and adhesion ability of ovarian cancer cells. Anoikis resistance of ovarian cancer cells was inhibited by KR through suppression of the p-STAT3/Bcl-2 axis. KR also increased the expression of FOXO3a. And inhibition of FOXO3a abrogated the effect of KR on integrin beta 1 and the p-STAT3/Bcl-2 axis in ovarian cancer. In addition, KR did not affect normal cells, even at high concentrations. These results revealed that activation of FOXO3a is a good target for ovarian cancer therapy, and that KR is a potential candidate compound for the treatment of ovarian cancer.
... For abdominal metastasis models, SKOV3 or ES-2 cells were harvested and resuspended in a mixed solution (50% Matrigel, Corning and 50% PBS). Next, 5×10 6 tumor cells in 200 µL were injected into intra-peritoneal cavity (1,32,33). About 20 days later, the mice underwent PET/CT imaging. ...
Ovarian cancer has the highest mortality rate of gynecologic malignancy. ¹⁸F-FDG positron emission tomography (PET) adds an important superiority over traditional anatomic imaging modalities in oncological imaging but has drawbacks including false negative results at the early stage of ovarian cancer, and false positives when inflammatory comorbidities are present. Aminopeptidase N (APN, also known as CD13) and integrin αvβ3 are two important targets overexpressed on tumor neo-vessels and frequently on ovarian cancerous cells. In this study, we used subcutaneous and metastatic models of ovarian cancer and muscular inflammation models to identify ⁶⁸Ga-NGR-RGD, a heterodimeric tracer consisting of NGR and RGD peptides targeting CD13 and integrin αvβ3, respectively, and compared it with ¹⁸F-FDG. We found that ⁶⁸Ga-NGR-RGD showed greater contrast in SKOV3 and ES-2 tumors than ¹⁸F-FDG. Low accumulation of ⁶⁸Ga-NGR-RGD but avid uptake of ¹⁸F-FDG were observed in inflammatory muscle. In abdominal metastasis models, PET imaging with ⁶⁸Ga-NGR-RGD allowed for rapid and clear delineation of both peritoneal and liver metastases (3-6 mm), whereas, ¹⁸F-FDG could not distinguish the metastasis lesions due to the relatively low metabolic activity in tumors and the interference of intestinal physiological ¹⁸F-FDG uptake. Due to the high tumor-targeting efficacy, low inflammatory uptake, and higher tumor-to-background ratios compared to that of ¹⁸F-FDG, ⁶⁸Ga-NGR-RGD presents a promising imaging agent for diagnosis, staging, and follow-up of ovarian tumors.
