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Ceramide synthase 6 predicts poor prognosis and activates the AKT/mTOR/4EBP1 pathway in high-grade serous ovarian cancer.

ABSTRACT: Objective: Ovarian cancer is one of the most common gynecological malignancies worldwide, and its mortality rate ranks first among gynecologic cancers. Ceramide synthases are closely related to cancer development. In this study, we investigated the role of ceramide synthase 6 (CerS6) in the development of serous ovarian cancer. Methods: Expression of CerS6 in cancerous and healthy ovarian tissue was assessed by database analysis and immunohistochemistry. The biological role of CerS6 in serous ovarian cancer cells was assessed by CerS6 knockdown followed by cell counting, colony formation, transwell migration, wound healing, and flow cytometry assays and measurement of tumor proliferation in nude mice. Signaling pathway components were analyzed by Western blotting. Gene enrichment was analyzed by GSEA and R, and RNA sequencing was used to compare the transcriptomes of serous ovarian cancer cells with and without CerS6 knockdown. Results: High CerS6 expression in ovarian cancer tissues was closely related to poor prognosis. Knockdown of CerS6 inhibited serous ovarian cancer cell proliferation, invasion, and metastasis and promoted their apoptosis. In addition, CerS6 knockdown increased the proportion of serous ovarian cancer cells in G2/M phase. CerS6 regulates cell cycle through the AKT/mTOR/4EBP1 signaling pathway, which affects cell proliferation and metastasis. The GSEA, R, and RNA sequencing analyses showed that knocking down CerS6 significantly affects cell cycle in serous ovarian cancer cells. Conclusions: CerS6 may have an oncogenic role in ovarian cancer and may represent a new prognostic marker and therapeutic target for serous ovarian cancer.

SUBMITTER: Shi Y

PROVIDER: S-EPMC7540095 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Ceramide synthase 6 predicts poor prognosis and activates the AKT/mTOR/4EBP1 pathway in high-grade serous ovarian cancer.

Shi Yinong Y Zhou Chen C Lu Huan H Cui Xiaoxiao X Li Jun J Jiang Shuheng S Zhang Hao H Zhang Rong R

American journal of translational research 20200915 9

<i>Objective:</i> Ovarian cancer is one of the most common gynecological malignancies worldwide, and its mortality rate ranks first among gynecologic cancers. Ceramide synthases are closely related to cancer development. In this study, we investigated the role of ceramide synthase 6 (CerS6) in the development of serous ovarian cancer. <i>Methods:</i> Expression of CerS6 in cancerous and healthy ovarian tissue was assessed by database analysis and immunohistochemistry. The biological role of CerS ...[more]

PMID: 33042469

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Project description:Recent studies have shown that the expression of ENPP1 is related to differentiation, death, dissemination and chemosensitivity of tumor cells. So far, there is no research in ovarian carcinoma. This study aimed at exploring the role of ENPP1 gene in ovarian carcinoma, the relationship with prognostic indicators and chemotherapy resistance, and investigates the possibility of molecular targeted therapy. The expression of ENPP1 in 41 normal ovarian epithelial tissues, 97 ovarian serous cystadenoma and 103 HGSOC tissues was detected by IHC. In ovarian cancer tissues and ovarian cancer cell lines, mRNA and protein expression of ENPP1 was determined by qRT-PCR and Western blot. The ENPP1 expression was knockdowned by siRNA. Cell proliferation was measured with the BrdU Cell Proliferation ELISA. Cell migration and invasion were detected by Wound-Healing, Transwell migration and Matrigel invasion assay. Caspase 3 activity was determined by the CaspACE. The expression of EMT markers such as E-cadherin, N-cadherin, and Vimentin was measured, and the expression of PCNA and MMP9 was also be detected. The results showed that the expression of ENPP1 was significantly increased in high-grade ovarian serous carcinoma, the number of strong expression was 85.4% (22.3%+63.1%) and only 1.03% (1.03%+0.0%) in serous cystadenoma, but no in normal ovarian epithelium (P< 0.05). And the stronger the expression of ENPP1, the later the FIGO stage and the poorer differentiation of cells (P = 0.001 or <0.001, respectively). However, no correlation was found between the expression of ENPP1 and chemosensitivity. ENPP1 was also highly expressed in ovarian cancer tissues and in epithelial ovarian cancer cell lines (A2780, CaoV3, OVCAR3, SKOV3 and 3ao). After down-regulation of ENPP1 expression by RNA interference, the cell proliferation, migration and invasion of ovarian cancer cell decreased significantly, the expression of apoptosis related gene caspase 3 increased significantly, while the expression of PCNA and MMP9 was significantly down regulated. In addition, EMT biological characteristics of A2780 and SKOV3 cells were also inhibited. In summary, the increased expression of ENPP1 may be related to the occurrence of HGSOC, and indicate that the disease progresses rapidly and the prognosis is poor. ENPP1 may be considered as a potential molecular therapeutic target.

Project description:BackgroundMitogen-activated protein kinase 4 (MAPK4) is an atypical member of the mitogen-activated protein kinase (MAPK) family. We report here that MAPK4 is overexpressed in glioma. The clinical significance, biological roles and underlying molecular mechanisms through which MAPK4 acts in glioma remain unclear.MethodsAnalysis of MAPK4 expression and associated survival in glioma patients was performed based on data obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases and confirmed in human glioma tissue by immunohistochemistry. MAPK4 function and pathway enrichment were analyzed through Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO). The viability and migration ability of MAPK4-silenced glioblastoma multiforme (GBM) cells were evaluated using CCK8 and transwell assays, respectively, and cell cycle and apoptosis analyses were performed using flow cytometry. Immunoblotting was used to analyze the protein level in MAPK4 knockdown glioma cells. We also analyzed the correlation of MAPK4 expression with immune infiltration and immune checkpoints in glioma.ResultsMAPK4 was overexpressed in IDH wild-type (wt) and 1p/19q non-codeletion gliomas. MAPK4 expression predicted poor prognosis of glioma patients. MAPK4 was significantly related to functional states, including stemness, metastasis, cell cycle, differentiation and proliferation, in glioma at single-cell resolution. MAPK4 silencing inhibited proliferation and migration and induced G1 cell cycle arrest in glioma cells via the AKT/mTOR pathway. In vivo, MAPK4 knockdown markedly suppressed the growth of primary glioma. In addition, MAPK4 expression correlated negatively with the infiltration of plasmacytoid DC cells, CD8+ T cells and T helper cells. Moreover, MAPK4 expression correlated positively with expression of the main immunoinhibitor checkpoint molecules and some chemokines in glioma.ConclusionMAPK4 functions as a prognostic indicator in glioma and promotes the proliferation and migration of GBM cells through the AKT/mTOR pathway. MAPK4 may participate in immune infiltration and the expression of immune checkpoints in the glioma microenvironment.

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Ceramide synthase 6 predicts poor prognosis and activates the AKT/mTOR/4EBP1 pathway in high-grade serous ovarian cancer.

Publications

Ceramide synthase 6 predicts poor prognosis and activates the AKT/mTOR/4EBP1 pathway in high-grade serous ovarian cancer.

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