title: MiR-744 functions as a proto-oncogene in nasopharyngeal carcinoma progression and metastasis via transcriptional control of ARHGAP5.
abstract: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastasis-prone epithelial cancer. The paucity of effective treatment strategies for recurrent and metastatic NPC is the major cause for stagnating survival rate of NPC. Therefore, it's urgent to understand the molecular mechanisms underlying NPC progression and identify novel avenues for targeted therapy. It has emerged recently that microRNAs are potential pro-tumorigenic or tumor-suppressive factors that participate in oncogenesis. In this study, we found that miR-744 expression was upregulated in NPC specimens compared to nasopharyngeal epithelium (NPE) tissue, and miR- 744 upregulation was significantly associated with TNM stage, tumorigenesis and metastasis. Functional studies revealed that miR-744 acts as a novel tumor promotor in NPC. Moreover, we determined that miR-744 targets ARHGAP5 (Rho GTPase activating protein 5), a protumorigenic gene, by directly interacting with its promoter and thereby regulating its expression at transcriptional level. Reintroduction of ARHGAP5 resembled the effects of miR-744 and silencing of ARHGAP5 clearly abrogated miR-744-induced enhancement of cell migration and invasion. High level of ARHGAP5 was positively correlated with that of miR-744 and with advanced stages of NPC, as well as with lymph node metastasis. Taken together, these data reveal for the first time that miR-744 exerts its proto-oncogenic function by directly targeting ARHGAP5 promoter. This newly identified miR-744/ARHGAP5 pathway provides further insight into the progression and metastasis of NPC and indicates potential novel therapeutic targets for NPC.
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Dianhe
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Nazmus
authors.initials: N
authors.lastname: Sakib
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Sha
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Song
mesh_terms: D000818:Animals; D002277:Carcinoma; D045744:Cell Line, Tumor; D018450:Disease Progression; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000502:physiology*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000556:secondary*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C513043:ARHGAP5 protein, human; D020690:GTPase-Activating Proteins; C000715470:MAS1 protein, human; C569733:MIRN744 microRNA, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins
keywords: ARHGAP5; metastasis; miR-744; nasopharyngeal carcinoma; tumorigenesis