Background: Ovarian cancer is the leading cause of gynecological cancer-related mortality. The novel oncogene S100A10 has been reported to be involved in cancer cell proliferation, invasion and metastasis. The role of S100A10 in ovarian cancer has not been well studied and the effect of S100A10 on chemotherapy remains unclear. The aims of the present study were to investigate the functional role of S100A10 in the progression and carboplatin sensitivity of ovarian cancer. Methods: We examined the expression levels in tissues of S100A10 in 138 cases of ovarian cancer by IHC. To determine the functional roles of downregulated S100A10 in ovarian cancer, cell proliferation, colony formation, cell migration and invasion assays were performed. Chemoresistance was analyzed by apoptosis assay. A xenograft tumor model was established to confirm the role of S100A10 in carboplatin resistance in vivo. Using Western blot assays, we also explored the possible mechanisms of S100A10 in ovarian cancer. Results: The results showed that increased expression of S100A10 was positively associated with carboplatin resistance (P < 0.001), tumor grade (P = 0.048) and a poorer prognosis (P = 0.0053). Functional analyses demonstrated that S100A10 suppression significantly suppressed ovarian cancer cell proliferation, colony formation, cell migration and invasion, remarkably increased carboplatin-induced apoptosis in SKOV3 and A2780 cells and inhibited tumor growth in vivo. Downregulation of S100A10 expression could inhibit cell proliferation and enhance ovarian cancer cell sensitivity to carboplatin, possibly involving the regulation of cleaved-Caspase3 and cleaved-PARP. Conclusions: Together, the results of the present study reveal that S100A10 expression can be used as a predictive marker for the prognosis of ovarian cancer and chemosensitivity to carboplatin.

Background: Ubiquitin specific protease 48 (USP48) is a member of the deubiquitinating enzymes (DUBs) family. However, the function of USP48 in ovarian cancer remains unclear. Objective: The present study reveals that USP48 knockdown could significantly inhibit cell migration and invasion in ES2, 3AO and A2780 cells, without affecting cell proliferation. Methods: After carboplatin (CBP) treatment, the USP48 ablation increases the apoptosis rate, and the cleaved PARP and cleaved caspase 3 expression levels in ES2, 3AO and A2780 cells. The subcutaneous tumor and intraperitoneally injected experiments demonstrated that the USP48 knockdown significantly increases responsiveness to CBP, and alleviates the metastasis in vivo. Meanwhile, USP48 deficiency results in the improved survival of mice. Results: Finally, the analysis of clinical samples and the TCGA and Kaplan-Meier Plot database revealed that the high expression of USP48 in ovarian cancer patients is associated with poor survival and resistance to CBP therapy. Conclusion: In summary, USP48 may be a potential therapeutic target for ovarian cancer patients.

DNA methylation regulators play critical roles in modulating oncogenic driver genes in cancers. However, the precise mechanisms through which these DNA methylation regulators influence oncogenesis and clinical therapy have yet to be fully elucidated. This study reveals that hypermethylation of under‐methylated regions (UMRs) within gene bodies is involved in the activation of oncogenic homeobox genes, particularly NKX2‐5 and LHX1, in esophageal squamous cell carcinoma (ESCC). Mechanistically, NKX2‐5 and LHX1 synergistically bind to the promoter region of UHRF1 , thereby augmenting its transcription. In turn, UHRF1 orchestrates the recruitment of DNMT1/DNMT3A, alongside NKX2‐5 and LHX1, to the UMRs of these genes, thereby increasing DNA methylation levels and their expression. This intricate interplay forms a positive transcriptional feedback loop between NKX2‐5/LHX1 and UHRF1, thus promoting the overexpression of all three genes and ultimately facilitating tumor growth. Notably, concurrent inhibition of UHRF1 and DNMTs impedes tumor growth by suppressing NKX2‐5 and LHX1 expression. Overall, this study identifies a positive feedback regulatory circuitry underlying the UMR hypermethylation‐mediated activation of oncogenic drivers in ESCC and proposes a promising therapeutic strategy for ESCC patients.

LHX2 dysregulations have been found to present in cancers, but the function of LHX2 in esophageal squamous cell carcinoma (ESCC) remains unknown. Here, we report that LHX2 was upregulated in ESCC tissues in comparison to the LHX2 levels in adjacent normal tissues. Loss- and gain-of-function experiments demonstrated that the knockdown of LHX2 markedly inhibited ESCC cells’ proliferation, migration, invasion, tumor growth and metastasis, whereas the overexpression of LHX2 had the opposite effects. A mechanistic investigation revealed that LHX2 bound to the promoter of SERPINE2 gene and transcriptionally regulated the expression of SERPINE2. Collectively, LHX2 facilitates ESCC tumor progression, and it could be a potential therapeutic target for ESCC.