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TNFRSF9 Suppressed the Progression of Breast Cancer via the p38MAPK/PAX6 Signaling Pathway.

ABSTRACT: Worldwide, breast cancer is the most common cancer in females. Endocrine therapy can effectively treat 85% of breast cancer patients, but 15% of patients could only be treated with chemotherapy and surgery, and the prognosis is much worse. Immunotherapy is the novel treatment for breast cancer, where PD-1 and CTLA-4 antibodies have shown evidence of immune modulation in breast cancer drug trials. In this study, we report that TNFRSF9 regulates the cell proliferation, invasion, and apoptosis of breast cancer cells through regulating the phosphorylation of p38, thus further regulating the expression of PAX6. In both breast cancer tissues and cell lines, the levels of TNFRSF9 are significantly decreased, and breast cancer cell development will be promoted with knockdown of TNFRSF9. Moreover, we identify that downregulation of TNFRSF9 can upregulate the phosphorylated p38 (p-p38) and PAX6. We further elucidate that p-p38 is essential for PAX6 expression as p38 phosphorylation inhibitor can reverse the upregulation of PAX6 and suppress cell proliferation and invasion and promote apoptosis in breast cancer cells. In summary, this study proposed a novel TNFRSF9/p38/PAX6 axis that contributes to tumor suppression, which suggests a potential immunotherapy target for breast cancer.

SUBMITTER: Liu X

PROVIDER: S-EPMC9256432 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe deubiquitinating (DUB) enzyme ubiquitin-specific protease 18 (USP18), also known as UBP43, is an ubiquitin-specific protease linked to several human malignancies. However, USP18's underlying function in human cervical cancer remains unclear. In the current study, we aimed to analyse the role of USP18 and its signalling pathways in cervical cancer.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to analyse USP18 levels in cervical cancer and matched to adjacent normal tissues. Moreover, RNA interference (RNAi) and lentiviral-mediated vector transfections were performed to silence and overexpress USP18, respectively, in cervical cancer cells. Further, Cell Counting Kit-8 (CCK-8) and Annexin V/PI staining assays were used to assess its biological function in cell proliferation and apoptosis, respectively. A xenograft model was used to examine USP18's function in vivo.ResultsThe present findings demonstrated that USP18 was overexpressed in cervical cancer specimens and cell lines. Silencing USP18 in SiHa and Caski cervical cancer cell lines inhibited cell proliferation, induced apoptosis, and promoted cleaved caspase-3 expression. In contrast, USP18 overexpression showed the opposite effects in human HcerEpic cells. A Gene Set Enrichment Analysis revealed that USP18 was enriched in the PI3K/AKT signalling pathway in cervical cancer. Hence, the PI3K/AKT inhibitor LY294002 was used to determine the relationship between USP18 and AKT in cervical cancer cells. Importantly, LY294002 significantly abolished the effects of USP18 overexpression in cervical cancer cells. In vivo, USP18 silencing inhibited human cervical cancer cells' tumorigenicity.ConclusionsThe current study indicates that USP18 is an oncogenic gene in cervical cancer. Our findings not only deepened the understanding of USP18's biological function in cervical cancer pathogenesis, but we also provided novel insight for cervical cancer therapy.Trial registrationRetrospectively registered.

Project description:PurposeCurrent knowledge of TMEM17, a recently identified protein of the transmembrane (TMEM) family, is limited, especially with respect to its expression and biological functions in malignant tumors. This study analyzed TMEM17 expression in invasive breast cancer tissue and breast cell lines and its relevance to clinicopathological factors, and investigated the mechanisms underlying the biological effects of TMEM17 on breast cancer cells.Patients and methodsTMEM17 protein expression was determined in 20 freshly harvested specimens (tumor and paired normal tissues) by Western blotting. Immunohistochemical analysis was performed to determine the expression and subcellular localization of TMEM17 in samples from 167 patients (mean age, 49 years) diagnosed with invasive ductal carcinoma (38 with triple-negative breast cancer; 129 with non-triple-negative breast cancer) who underwent complete resection in the First Affiliated Hospital of China Medical University between 2011 and 2013. Furthermore, TMEM17 was knocked down by small interfering RNAs in breast cancer cell lines.ResultsTMEM17 was found to be significantly upregulated in breast cancer tissues compared to the corresponding normal breast tissues by Western blotting (p=0.015). Immunohistochemical analysis revealed that TMEM was significantly upregulated in invasive breast cancer cells compared to adjacent normal breast duct glandular epithelial cells (10.78% vs 76.05%, p<0.001), and its expression was closely related to the patient's T-stage (p=0.022), advanced TNM stages (p=0.007), and lymph node metastasis (p=0.012). After TMEM17 knockdown or overexpression in breast cancer cell lines, TMEM17 upregulated p-AKT, p-GSK3β, active β-catenin, and Snail, and downstream target proteins c-myc and cyclin D1, and downregulated E-cadherin, resulting in increased cancer cell proliferation, invasion, and migration. These effects were reversed by the AKT inhibitor LY294002.ConclusionOur results indicate that TMEM17 is upregulated in breast cancer tissues and can promote malignant progression of breast cancer cells by activating the AKT/GSK3β signaling pathway.

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TNFRSF9 Suppressed the Progression of Breast Cancer via the p38MAPK/PAX6 Signaling Pathway.

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