title: miR-2861 acts as a tumor suppressor via targeting EGFR/AKT2/CCND1 pathway in cervical cancer induced by human papillomavirus virus 16 E6.
abstract: Persistent infection with oncogenic human papillomavirus viruses (HPVs) is a casual factor for cervical cancer and its precursors, and the abnormal constitutive expression of viral oncoprotein E6 is a key event during the malignant transformation. Here, we performed miRNA microarray to identify changes of miRNAs following ectopic HPV16 E6 overexpression in HEK293T cells and found miR-2861 was greatly decreased in both HEK293T and HaCaT cells expressing HPV16 E6 compared to vector control. Further, we demonstrated a biological link among HPV16 E6, miR-2861, EGFR, AKT2, and CCND1 in cervical cancer cells. We showed that miR-2861 was downregulated in cervical cancer tissues and negatively correlated with advanced tumor stage and lymph node metastasis. Overexpression of miR-2861 suppressed cervical cancer cell proliferation and invasion and enhanced apoptosis. Subsequent investigation revealed that EGFR, AKT2, and CCND1 were all the direct targets of miR-2861. Importantly, silencing EGFR, AKT2, and/or CCND1 recapitulated the cellular effects seen upon miR-2861 overexpression. Restoration of EGFR, AKT2, and/or CCND1 counteracted the effects of miR-2861 expression. Thus, we identified a new pathway employing miR-2861, EGFR, AKT2, and CCND1 that may mediate HPV16 E6 induced initiation and progression of cervical cancer.
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
authors.forename: Junfen
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wan
authors.affiliation: Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Lu
mesh_terms: D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D052162:Human papillomavirus 16 / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism; D030361:Papillomavirus Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology
chemical_list: C530104:CCND1 protein, human; C068651:E6 protein, Human papillomavirus type 16; C583983:MIRN2861 microRNA, human; D035683:MicroRNAs; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D019938:Cyclin D1; C512478:EGFR protein, human; D066246:ErbB Receptors; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt