Abstract
Cervical cancer is one of the most lethal types of cancer in female. Aberrant activation of Wnt/β-catenin signaling pathway has been found to be involved in cervical cancer development and progression, whereas the underlying molecular mechanisms remain poorly understood. The present study showed that NHERF1 was a novel gene associated with both cell proliferation and Wnt signaling pathway in cervical cancer by analysis of differential gene expression and gene cluster for the cervical cancer specimens from GEO data sets. It was further demonstrated in cellular study that NHERF1 inhibition of cervical cancer cell proliferation through Wnt/β-catenin signaling was dependent on α-actinin-4 (ACTN4) expression. A negative association between NHERF1 expression and levels of ACTN4 and β-catenin was found in mouse xenograft model and cervical cancer specimens. Low levels of NHERF1 in cervical cancer specimens were found to associate with activation of cell proliferation and Wnt/β-catenin signaling by gene set enrichment analysis, and also were an independent predictive factor for worse prognosis of cervical cancer patients by Cox regression analysis. These findings demonstrate that NHERF1 inhibits Wnt signaling-mediated proliferation of cervical cancer via suppression of ACTN4, and NHERF1 downregulation may contribute to the progression of cervical cancer. These findings may also shed some lights for understanding the underlying mechanisms of cisplatin resistance and worse prognosis of HPV-inactive cervical cancer patients.
Highlights
Cervical cancer is the fourth most common cancer in women worldwide with 500,000 new cases and 233,000 deaths per year, and the second leading cause of cancer death for women living in developing countries[1]
NHERF1 is a novel downregulated gene correlated with cell proliferation and Wnt signaling in cervical cancer
Functional clustering analysis of these 1615 genes revealed that 19 genes were involved in Wnt pathway, and 38 genes participated in negative regulation of cell proliferation
Summary
Cervical cancer is the fourth most common cancer in women worldwide with 500,000 new cases and 233,000 deaths per year, and the second leading cause of cancer death for women living in developing countries[1]. HPV-infected patients develop cancer, and factors such as genetic and epigenetic changes acting synergistically have been implicated to the progression from cervical precancerous lesions to cervical cancer[2]. Uncontrolled cellular proliferation caused by dysregulation of several major molecular signaling pathways is a major feature of cervical epithelial malignancy[3,4]. In the past decades, increasing evidences suggested that aberrant activation of Wingless-type (Wnt)/β-catenin pathway plays major roles during the multistep processes, including cell proliferation and metastasis in cervical cancer carcinogenesis and progression[10,11]. HR-HPV is a key factor during cervical cancer development, and hyperactivation of Wnt pathway has been demonstrated in HPV-associated cancers[12,13]. The activation of Wnt signaling induced by HPV oncoproteins, such as E6 and
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