Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Alice Gambelli
PROVIDER: S-SCDT-10_1038-S44321-024-00069-3 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Ovarian cancer (OC), the second most common form of gynecologic malignancy, has a poor prognosis and is often discovered in the late stages. Platinum-based chemotherapy is the first line of therapy. Nevertheless, treatment OC has proven challenging due to toxicity and the development of acquired resistance to therapy. Tumor microenvironment (TME) has been associated with platinum chemoresistance. Malignant ascites has been used as OC tumor microenvironment and its ability to induce platinum chemoresistance has been investigated. Our results suggest that exposure to OC ascites induces platinum chemoresistance in 11 of 13 cases (85 %) on OC cells. In contrast, 75 % of cirrhotic ascites (3 of 4) failed to confer platinum chemoresistance to OC cells. Cytokine array analysis revealed that IL -6 and to a lesser extent HGF were enriched in OC ascites, whereas IL -22 was enriched in cirrhotic ascites. Pharmaceutical inhibitors targeting the IL -6/ JAK pathway were mildly effective in overcoming platinum chemoresistance induced by malignant ascites. In contrast, crizotinib, an HGF/c- MET inhibitor, and 2-hydroxyestradiol (2HE2) were effective in restoring platinum chemosensitivity to OC. Our results demonstrate the importance of OC ascites in supporting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity of OC cells.
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Project description:Ovarian cancer is the fifth most deadly cancer in women in the United States and despite advances in surgical and chemotherapeutic treatments survival rates have not significantly improved in decades. The poor prognosis for ovarian cancer patients is largely due to the extremely high (80%) recurrence rate of ovarian cancer and because the recurrent tumors are often resistant to the widely utilized platinum-based chemotherapeutic drugs. In this study, expression of Rad6, an E2 ubiquitin-conjugating enzyme, was found to strongly correlate with ovarian cancer progression. Furthermore, in ovarian cancer cells Rad6 was found to stabilize ?-catenin promoting stem cell-related characteristics, including expression of stem cell markers and anchorage-independent growth. Cancer stem cells can promote chemoresistance, tumor recurrence and metastasis, all of which are limiting factors in treating ovarian cancer. Thus it is significant that Rad6 overexpression led to increased resistance to the chemotherapeutic drug carboplatin and correlated with tumor cell invasion. These findings show the importance of Rad6 in ovarian cancer and emphasize the need for further studies of Rad6 as a potential target for the treatment of ovarian cancer.
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Project description:BackgroundColorectal cancer (CRC), a prevalent gastrointestinal malignant disease, causes substantial morbidity and mortality. Identification of novel prognostic biomarkers and therapeutic targets is critically needed to improve patient outcomes. Although solute carrier family 12 member 8 (SLC12A8) has high expression in various tumors and affects tumor progression, its role in CRC remains unclear. The aim of this study was to investigate the functions of SLC12A8 in CRC.MethodsSLC12A8 expression and its association with clinical significance in CRC patients were explored via multiple public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), The Human Protein Atlas (HPA), The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), and Kaplan-Meier plotter. The effects of SLC12A8 on the CRC cell apoptosis, epithelial-mesenchymal transition (EMT), reactive oxygen species (ROS) production, and sensitivity to oxaliplatin were verified by in vitro experiments.ResultsSLC12A8 expression was upregulated in CRC tissues compared with normal colorectal tissues. Furthermore, high expression of SLC12A8 was associated with poorer prognosis in CRC patients. Pathway enrichment analyses revealed SLC12A8 involvement in oxidative stress and transforming growth factor-beta (TGF-β) signaling. Experiments in CRC cells showed that SLC12A8 upregulation promoted apoptosis resistance, EMT, and inhibited ROS production. Moreover, SLC12A8 knockdown enhanced the sensitivity of CRC cells to oxaliplatin chemotherapy.ConclusionsOur integrative analyses identify SLC12A8 as a candidate biomarker for CRC progression. Targeting SLC12A8 may improve patient responses to oxaliplatin-based treatment regimens.
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Project description:Ovarian cancer is the most frequent cause of death among gynecologic malignancies. A total of 80% of patients who have completed platinum-based chemotherapy suffer from relapse and develop resistance within 2 years. In the present study, we obtained patients' complete platinum (cisplatin and carboplatin) medication information from The Cancer Genome Atlas database and then divided them into two categories: resistance and sensitivity. Difference analysis was performed to screen differentially expressed genes (DEgenes) related to platinum response. Subsequently, we annotated DEgenes into the protein-protein interaction network as seed nodes and analyzed them by random walk. Finally, second-ranking protease serine 1 gene (PRSS1) was selected as a candidate gene for verification analysis. PRSS1's expression pattern was continuously studied in Oncomine and cBio Cancer Genomic Portal databases, revealing the key roles of PRSS1 in ovarian cancer formation. Hereafter, we conducted in-depth explorations on PRSS1's platinum response to ovarian cancer through tissue and cytological experiments. Quantitative real-time polymerase chain reaction and Western blot assay results indicated that PRSS1 expression levels in platinum-resistant samples (tissue/cell) were significantly higher than in samples sensitive to platinum. By cell transfection assay, we observed that knockdown of PRSS1 reduced the resistance of ovarian cancer cells to cisplatin. Meanwhile, overexpression of PRSS1 increased the resistance to cisplatin. In conclusion, we identified a novel risk gene PRSS1 related to ovarian cancer platinum response and confirmed its key roles using multiple levels of low-throughput experiments, revealing a new treatment strategy based on a novel target factor for overcoming cisplatin resistance in ovarian cancer.
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