Dataset Information

TMTC1 promotes invasiveness of ovarian cancer

ABSTRACT: Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Although O-mannosyltransferase TMTC1 is highly expressed by ovarian cancer, its pathophysiologic role in ovarian cancer remains unclear. Here, immunohistochemistry showed that TMTC1 was overexpressed in ovarian cancer tissues compared with the adjacent non-tumor ovarian tissues and high TMTC1 expression was associated with poor prognosis in patients with ovarian cancer. Silencing TMTC1 reduced ovarian cancer cell viability, migration, and invasion in vitro as well as suppressed peritoneal tumor growth and metastasis in vivo. Moreover, TMTC1 knockdown reduced cell-laminin adhesion, which was associated with the decreased phosphorylation of FAK at pY397. Conversely, TMTC1 overexpression promoted these malignant properties in ovarian cancer cells. Glycoproteomic analysis and Concanavalin A (ConA) pull-down assays showed that integrins β1 and β4 were novel O-mannosylated protein substrates of TMTC1. Furthermore, TMTC1-mediated cell migration and invasion were significantly reversed by siRNA-mediated knockdown of integrin β1 or β4. Collectively, these results suggest that TMTC1-mediated invasive behaviors are primarily through integrins β1 and β4 and that TMTC1 is a potential therapeutic target for ovarian cancer.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Hsin-Yi Wu

LAB HEAD: Min-Chuan Huang

PROVIDER: PXD037907 | Pride | 2023-10-24

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20190603_1274_NTUHMCHuang_Control.raw	Raw
	20190603_1274_NTUHMCHuang_Hex.msf	Msf
	20190603_1276_NTUHMCHuang_TMTC1.raw	Raw

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Publications

TMTC1 promotes invasiveness of ovarian cancer cells through integrins β1 and β4.

Yeh Ting-Chih TC Lin Neng-Yu NY Chiu Chin-Yu CY Hsu Tzu-Wen TW Wu Hsin-Yi HY Lin Hsuan-Yu HY Chen Chi-Hau CH Huang Min-Chuan MC

Cancer gene therapy 20230523 8

Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Although O-mannosyltransferase TMTC1 is highly expressed by ovarian cancer, its pathophysiological role in ovarian cancer remains unclear. Here, immunohistochemistry showed that TMTC1 was overexpressed in ovarian cancer tissues compared with adjacent normal ovarian tissues, and high TMTC1 expression was associated with poor prognosis in patients with ovarian cancer. Silencing TM ...[more]

PMID: 37221403

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Project description:Epithelial ovarian cancer (EOC) accounts for 4% of all cancers in women and is the leading cause of death from gynecologic malignancies. It is well established that cancer invasion and metastasis still represent the major causes of the failure of cancer treatment. Previously, we identified the mannose receptor LY75 (DEC205/CD205) gene as notably hypomethylated in high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. LY75 has been identified as a putative antigen-uptake receptor, which is expressed abundantly on dendritic cells, which are specialist antigen presenting cells to T lymphocytes for the initiation of an immune response. The implication of LY75 in EOC tumorigenesis is currently unknown. Here we show that LY75 is strongly overexpressed in HG serous EOC tumors as compared to normal ovarian tissue. Importantly, shRNA-mediated LY75 knockout in the mesenchymal EOC cells (SKOV3) led to mesenchymal to epithelial transition (MET), associated with overexpression of epithelial markers E-cadherin and EPCAM and loss of expression of mesenchymal markers Fibronectin, N-cadherin Snail1 and Twist1. In addition, LY75 suppression significantly inhibited EOC cell migration and invasion in vitro. However, LY75 knockdown led to enhanced tumor cell dissemination and significantly increased lethality in vivo, in xenograft model of advanced peritoneal EOC. Thus, our findings indicate that LY75 could play an essential role in the mesenchymal-to-epithelial transition (MET) of EOC cells and support the hypothesis that, while epithelial-to-mesenchymal transition (EMT) enables the invasiveness of tumor cells, a MET-associated epithelial phenotype could be essential for their metastatic colonization. To better understand the molecular mechanisms of LY75 gene action in epithelial ovarian cancer (EOC), we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon LY75 suppression in SKOV3 EOC cells. We compared the gene expression of the previously selected shRNA-mediated LY75-knockdown clones sh-S3 and sh-S6 against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for each of the LY75-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.