Integrating single-cell RNA sequencing and prognostic model revealed the carcinogenicity and clinical significance of FAM83D in ovarian cancer

Abstract

BackgroundOvarian cancer (OC) is a fatal gynecological tumor with high mortality and poor prognosis. Yet, its molecular mechanism is still not fully explored, and early prognostic markers are still missing. In this study, we assessed carcinogenicity and clinical significance of family with sequence similarity 83 member D (FAM83D) in ovarian cancer by integrating single-cell RNA sequencing (scRNA-seq) and a prognostic model.MethodsA 10x scRNA-seq analysis was performed on cells from normal ovary and high-grade serous ovarian cancer (HGSOC) tissue. The prognostic model was constructed by Lasso-Cox regression analysis. The biological function of FAM83D on cell growth, invasion, migration, and drug sensitivity was examined in vitro in OC cell lines. Luciferase reporter assay was performed for binding analysis between FAM83D and microRNA-138-5p (miR-138-5p).ResultsOur integrative analysis identified a subset of malignant epithelial cells (C1) with epithelial-mesenchymal transition (EMT) and potential hyperproliferation gene signature. A FAM83D+ malignant epithelial subcluster (FAM83D+ MEC) was associated with cell cycle regulation, apoptosis, DNA repair, and EMT activation. FAM83D resulted as a viable prognostic marker in a prognostic model that efficiently predict the overall survival of OC patients. FAM83D downregulation in SKOV3 and A2780 cells increased cisplatin sensitivity, reducing OC cell proliferation, migration, and invasion. MiR-138-5p was identified to regulate FAM83D’s carcinogenic effect in OC cells.ConclusionsOur findings highlight the importance of miR-138 -5p/FAM83D/EMT signaling and may provide new insights into therapeutic strategies for OC.

The FBXW7-binding sites on FAM83D are potential targets for cancer therapy

“…FAM83D gene is located on chromosome 20q which is frequently amplified thus resulting in high expression in the majority of human cancer types including ovarian cancer, colorectal cancer, gastric cancer, esophageal cancer, lung cancer, breast cancer, hepatocellular carcinoma and pancreatic adenocarcinoma [ 11 , 13 , 16 – 20 , 22 , 35 , 36 ]. Over-expressed FAM83D promotes neoplastic transformation and positively correlates to aggressive tumor biology, high-grade tumors, and poor prognosis in a variety of cancers [ 13 , 16 , 20 , 37 , 38 ]. It has been reported that FAM83D exerts its oncogenic roles through activating critical signaling pathways.…”

“…Functional analysis further revealed that H343/L344 double mutations failed to decrease FBXW7 expression and remarkably ameliorated the tumor-promotive effects of FAM83D both in vitro and in vivo, highlighting the importance of these sites in biological activities of FAM83D. Since we and other have shown that overexpression of FAM83D confers poor prognosis and resistance to chemotherapy and other cancer treatments [ 16 , 37 ], future studies may shed more lights on whether and how targeting the FBXW7-binding sites on FAM83D will have good curative effect against multiple cancer types.…”

Single-cell and spatial transcriptome sequencing uncover a platinum-resistant cluster overexpressed TACSTD2 in high-grade serous ovarian cancer

“…Human ovarian cancer cell lines (SKOV3, A2780, CAOV8, CAOV3) as well as ovarian surface epithelial cells (OSE) were cultured using previously established protocols and authenticated by the STR method 18 . SKOV3 and CAOV3 were used for specific experiments.…”

“…Flow cytometry analysis was performed following established protocols outlined in previous studies 18 . Cells were treated with a final concentration of 10 μg/ml of cisplatin for 48 h. The BD FACSCanto and Beckman Coulter instruments were used.…”