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Abstract
Cervical cancer (CC) is a malignant solid tumor, which is one of the main causes of morbidity and mortality in women. Persistent High-risk human papillomavirus (hrHPV) infection is closely related to cervical cancer and autophagy has been suggested to inhibit viral infections. miRNAs have been reported to regulate autophagy in many solid tumors with many studies implicating miR-224-3p in the regulation of autophagy. In this study, we performed a miRNA microarray analysis on CC tissues and found that a large number of miRNAs with differential expressions in hrHPV-infected tissues. We identified miR-224-3p as a candidate miRNA selectively up regulated in HPV-infected tissues and cell lines. Further analysis revealed that miR-224-3p regulates autophagy in cervical cancer tissues and cell lines. While the overexpression of miR-224-3p inhibits autophagy in HPV-infected cells, knocking down endogenous miR-224-3p increases autophagy activity in the same cells. In addition, we found that miR-224-3p directly inhibits the expression of autophagy related gene, FAK family-interacting protein of 200 kDa (FIP200). In summary, we found that miR-224-3p regulates autophagy in hrHPV-induced cervical cancer cells through targeting FIP200 expression.
Highlights
Cervical Cancer (CC) is a common gynecological malignancy and a leading cause of cancer-associated mortality in females, especially in developing countries[1]
To identify candidate miRNAs whose expression levels are altered in association with High-risk human papillomavirus (hrHPV) infection, we conducted a miRNA microarray screen using 150 clinical samples collected from patients diagnosed with various stages of HPV-induced cervicitis as well as from patients with non-HPV-associated cervicitis
Autophagy has been frequently linked to cancer pathogenesis with many tumors observed to have dysregulated autophagic activity[19,20]
Summary
Cervical Cancer (CC) is a common gynecological malignancy and a leading cause of cancer-associated mortality in females, especially in developing countries[1]. The viral oncogenes E6 and E7, especially from the high-risk HPV-16 or/and HPV-18 subtypes are the main mediators of HPV-induced tumorigenesis and play key roles in CC pathogenesis[4,5]. Expression of these oncoproteins result in the loss of function of host tumor-suppressor proteins, causing abnormalities in cell cycle regulation and host-cell biological activity. It was recently suggested that host cells could utilize the autophagy process to protect against viral infections[8] This exciting finding leads us to hypothesize that molecular interventions that increase cellular autophagy levels could enhance host cell resistance to hrHPV infections. A growing body of evidence is implicating miRNAs in the regulation of autophagy and further studies into the role of miRNAs in the control of autophagy will expand our knowledge on the molecular mechanisms behind miRNA-mediated autophagy regulation
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