NUF2 overexpression contributes to epithelial ovarian cancer progression via ERBB3-mediated PI3K-AKT and MAPK signaling axes

Abstract

IntroductionNDC80 kinetochore complex component (NUF2) is upregulated and plays an important role in various human cancers. However, the function and mechanism of NUF2 in epithelial ovarian cancer (EOC) remain unclear.MethodsNUF2 expression was detected in EOC tissues and cell lines. The effects of NUF2 downregulation on cell proliferation, migration and invasion in EOC were analyzed by CCK-8 and Transwell assays. Meanwhile, the effect of NUF2 downregulation on tumor growth in vivo was determined by xenograft tumor models. The mechanisms by which NUF2 regulates EOC progression were detected by RNA sequencing and a series of in vitro assays.ResultsWe showed that NUF2 was significantly upregulated in EOC tissues and cell lines, and high NUF2 expression was associated with FIGO stage, pathological grade and poor EOC prognosis. NUF2 downregulation decreased cell proliferation, migration, invasion and tumor growth in nude mice. RNA sequencing studies showed that NUF2 knockdown inhibited several genes enriched in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT serine/threonine kinase (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways. Erb-B2 receptor tyrosine kinase 3 (ERBB3) was the key factor involved in both of the above pathways. We found that ERBB3 silencing could inhibit EOC progression and repress activation of the PI3K-AKT and MAPK signaling pathways. Furthermore, the exogenous overexpression of ERBB3 partially reversed the inhibitory effects on EOC progression induced by NUF2 downregulation, while LY294002 and PD98059 partially reversed the effects of ERBB3 upregulation.ConclusionThese results showed that NUF2 promotes EOC progression through ERBB3-induced activation of the PI3K-AKT and MAPK signaling axes. These findings suggest that NUF2 might be a potential therapeutic target for EOC.

NUF2 regulated the progression of hepatocellular carcinoma through modulating the PI3K/AKT pathway via stabilizing ERBB3

“…Previous studies have indicated that NUF2 can regulate ERBB3 expression in the context of epithelial ovarian cancer progression via the PI3K-AKT and MAPK signaling axes [12] . However, the specific mechanism by which NUF2 regulates ERBB3 expression has not been extensively investigated in HCC.…”

Comprehensive molecular analyses and experimental validation of CDCAs with potential implications in kidney renal papillary cell carcinoma prognosis

“…KIRP, the second most prevalent subtype of renal cell carcinoma, is usually detected incidentally during routine physical examinations [ 30 ]. Recently, a substantial body of evidence has suggested that CDCA genes are correlated with cancer occurrence, progression, and prognosis [ 8 , 16 ]. However, there are currently few studies on their roles in KIRP.…”

“…Previous studies have demonstrated that any disorder in cell division can lead to cancer onset and progression [ 6 , 7 ]. Furthermore, previous reports have suggested that the aberrant expression of CDCAs is strongly correlated with some human cancers, including ovarian cancer [ 8 ], hepatocellular carcinoma [ 9 ], prostate cancer [ 10 ], nasopharyngeal carcinoma [ 11 ], breast cancer [ 12 ], pancreatic adenocarcinoma [ 13 ], stomach carcinoma [ 14 ], hypopharyngeal squamous cell carcinoma [ 15 ], and non-small cell lung cancer [ 16 ]. Notably, few studies have described the relationship between certain members of the CDCA family and the immune microenvironment.…”