VSTM2L contributes to anoikis resistance and acts as a novel biomarker for metastasis and clinical outcome in ovarian cancer

The majority of patients are diagnosed when ovarian cancer (OC) has metastasized, making surgery and chemotherapy less effective. Thus, there is an urgent need to elucidate the mechanisms underlying metastasis and to further explore novel diagnostic biomarkers of OC metastasis. Here, we conducted a genome-wide CRISPR-Cas9 screen for anoikis resistance to identify key genes associated with OC metastasis. Further, bioinformatic analysis was performed using TCGA and GTEx datasets to explore the genes associated with OC progression and prognosis. After integrated analysis, the V-set and transmembrane domain-containing protein 2-like (VSTM2L) was identified as a crucial gene closely associated with OC metastasis, progression, and prognosis. Further validation using a patient-based cohort suggested that VSTM2L expression was significantly higher in metastatic lesions than in primary lesions. Subsequently, an in vitro assay showed that VSTM2L silencing increased SKOV3 cell death and hampered spheroid formation. Mechanistically, GSEA highlighted that epithelial-mesenchymal transition (EMT)-related pathways was positively associated with VSTM2L expression. Consistently, the validation based on the VSTM2L silence suggested the involvement of VSTM2L in EMT-related TGF-beta and NF-kappa B signaling. Meanwhile, the addition of VSTM2L-containing medium did not provoke those signaling, indicating VSTM2L functions as an intracellular protein to activate TGF-beta and NF-kappa B signaling. In summary, our study revealed that VSTM2L is a novel player involved in anoikis resistance and is a promising biomarker of OC metastasis and prognosis.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

In this study, VSTM2L was identified as a crucial gene associated with ovarian cancer (OC) metastasis, progression, and prognosis. Further experiments showed that silencing VSTM2L increased cell death and inhibited spheroid formation in SKOV3 cells. Mechanistically, VSTM2L was found to be involved in EMT-related TGF-beta and NF-kappa B signaling pathways. These findings highlight VSTM2L as a novel biomarker for OC metastasis and prognosis.