Abstract
Cervical cancer is one of the most common female malignancies, and cisplatin-based chemotherapy is routinely utilized in locally advanced cervical cancer patients. However, resistance has been the major limitation. In this study, we found that Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) was downregulated in cisplatin-resistant cells. Analysis based on a cervical cancer dataset from The Cancer Genome Atlas (TCGA) showed association of NHERF1 expression with disease-free survival of patients received cisplatin treatment. NHERF1 overexpression inhibited proliferation and enhanced apoptosis in cisplatin-resistant HeLa cells, whereas NHERF1 knockdown had inverse effects. While parental HeLa cells were more resistant to cisplatin after NHERF1 knockdown, NHERF1 overexpression in CaSki cells promoted cisplatin sensitivity. Overexpression and knockdown studies also showed that NHERF1 significantly inhibited AKT and extracellular signal–regulated kinase (ERK) signaling pathways in cisplatin-resistant cells. Taken together, our results provide the first evidence that NHERF1 can sensitize cisplatin-refractory cervical cancer cells. This study may help to increase understanding of the molecular mechanisms underlying cisplatin resistance in tumors.
Highlights
Cervical cancer is the second most common malignancy in women, accounting for an estimated 12,990 new cases and 4120 deaths in the USA for 2016
Since cisplatin resistance was generally associated with increased cisplatin export [17], we first analyzed the expression profile of genes annotated to regulation of cell excretion in a dataset GSE15120 from the Gene Expression Omnibus (GEO)
Gene Set Enrichment Analysis (GSEA) on the The Cancer Genome Atlas (TCGA) cervical cancer dataset showed that the genes related to cisplatin resistance were correlated with Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) expression (Figure 1C,D)
Summary
Cervical cancer is the second most common malignancy in women, accounting for an estimated 12,990 new cases and 4120 deaths in the USA for 2016. About one third of patients with invasive cervical cancer died of metastasis [1]. Cisplatin remains the cornerstone in the systemic anti-neoplastic management of locally advanced cervical cancer (LACC). The agent has shown efficacy in the treatment of this disease, resistance is a major limitation. The median duration of measurable response is only several months in chemotherapy-naïve patients [2]. Patients with recurrent disease have a poor prognosis with a one-year survival rate between 15% and 20% [3]. Defining the regulatory mechanisms underlying cisplatin resistance has been an emerging line of research
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