Abstract
Ectopic glucose-6-phosphate dehydrogenase (G6PD) expression may contribute to tumorigenesis in cervical cancer associated with high-risk human papillomavirus (HR-HPV 16 and 18) infections. Here, we demonstrate that microRNA-1 (miR-1) in association with AGO proteins targets G6PD in HR-HPV-infected human cervical cancer cells. miR-1 inhibited expression of a reporter construct containing a putative G6PD 3′-UTR seed region and suppressed endogenous G6PD expression. Down-regulation of miR-1 increased G6PD expression in cervical cancer cells. Regression analysis revealed that miR-1 levels correlate negatively with the clinicopathologic features in HR-HPV 16/18-infected cervical cancer patients. miR-1 overexpression inhibited proliferation and promoted apoptosis in cervical cancer cells and reduced xenograft tumor growth in nude mice. Conversely, sponge-mediated miR-1 knockdown markedly increased viability and reduced apoptosis in cervical cancer cells and supported neoplasm growth. Restoration of G6PD expression partially reversed the effects of miR-1 overexpression both in vitro and in vivo. In addition, co-transfection of G6PD siRNA and miR-1 sponge partially reversed miR-1 sponge-induced reductions in cell viability and neoplasm growth. These results suggest that miR-1 suppresses the development and progression of HR-HPV 16/18-infected cervical cancer by targeting G6PD and may be a promising novel therapeutic candidate.
Highlights
In 2008, cervical cancer was the third most common malignant cancer, accounting for 9% of new cases (529,800), and the fourth leading cause of cancerrelated death, accounting for 8% of such deaths, among women worldwide [1]
We previously demonstrated that overexpression of Glucose-6-phosphate dehydrogenase (G6PD) in cervical cancer was positively correlated with cervical cancer development in patients infected with high-risk human papillomaviruses (HR-HPV) 16/18 [5]
Our results demonstrate that miR-1 inhibited G6PD expression in human cervical cancer cells and tumors
Summary
In 2008, cervical cancer was the third most common malignant cancer, accounting for 9% of new cases (529,800), and the fourth leading cause of cancerrelated death, accounting for 8% of such deaths, among women worldwide [1]. Persistent high-risk human papillomaviruses (HR-HPV) are the most important etiologic agent in cervical cancer pathogenesis [2, 3]. HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 are considered HR or oncogenic types due to their occurrence in high-grade squamous intraepithelial lesions or cervical cancer [4]. Our previous data indicated that elevated G6PD levels were positively correlated with cervical carcinogenesis in 30 to 40-year-old women infected with HR-HPV-16/18. G6PD knockdown decreased proliferative capacity and increased apoptosis in both HPV16+ Siha and HPV18+ Hela cells [5]. These data suggest that G6PD overexpression might contribute to the development and growth of HR-HPV 16/18-associated cervical cancer. The sources and regulators of ectopic G6PD expression in carcinogenic events of HR-HPV-16/18associated cervical cancer, remain unknown
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