title: MicroRNA-377 suppresses initiation and progression of esophageal cancer by inhibiting CD133 and VEGF.
abstract: Esophageal cancer is one of the most lethal cancers worldwide with poor survival and limited therapeutic options. The discovery of microRNAs created a new milestone in cancer research. miR-377 is located in chromosome region 14q32, which is frequently deleted in esophageal squamous cell carcinoma (ESCC), but the biological functions, clinical significance and therapeutic implication of miR-377 in ESCC are largely unknown. In this study, we found that miR-377 expression was significantly downregulated in tumor tissue and serum of patients with ESCC. Both tumor tissue and serum miR-377 expression levels were positively correlated with patient survival. Higher serum miR-377 expression was inversely associated with pathologic tumor stage, distant metastasis, residual tumor status and chemoradiotherapy resistance. The roles of miR-377 in suppressing tumor initiation and progression, and the underlying molecular mechanisms were investigated. Results of in vitro and in vivo experiments showed that miR-377 overexpression inhibited the initiation, growth and angiogenesis of ESCC tumors as well as metastatic colonization of ESCC cells, whereas silencing of miR-377 had opposite effects. Mechanistically, miR-377 regulated CD133 and VEGF by directly binding to their 3' untranslated region. Moreover, systemic delivery of formulated miR-377 mimic not only suppressed tumor growth in nude mice but also blocked tumor angiogenesis and metastasis of ESCC cells to the lungs without overt toxicity to mice. Collectively, our study established that miR-377 plays a functional and significant role in suppressing tumor initiation and progression, and may represent a promising non-invasive diagnostic and prognostic biomarker and therapeutic strategy for patients with ESCC.
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.|Centre for Cancer Research, The University of Hong Kong, Pokfulam, China.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.
authors.forename: W W
authors.initials: WW
authors.lastname: Xu
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.
authors.forename: L
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Surgery, The University of Hong Kong, Pokfulam, China.
authors.forename: K T
authors.initials: KT
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.|Centre for Cancer Research, The University of Hong Kong, Pokfulam, China.
authors.forename: S W
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: Centre for Cancer Research, The University of Hong Kong, Pokfulam, China.|Department of Surgery, The University of Hong Kong, Pokfulam, China.
authors.forename: N P Y
authors.initials: NPY
authors.lastname: Lee
authors.affiliation: Centre for Cancer Research, The University of Hong Kong, Pokfulam, China.|Department of Surgery, The University of Hong Kong, Pokfulam, China.
authors.forename: S
authors.initials: S
authors.lastname: Law
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: L Y
authors.initials: LY
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: E M
authors.initials: EM
authors.lastname: Li
authors.affiliation: The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.|Centre for Cancer Research, The University of Hong Kong, Pokfulam, China.|Department of Pathology, The University of Hong Kong, Pokfulam, China.
authors.forename: K W
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Department of Clinical Oncology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
authors.forename: Y R
authors.initials: YR
authors.lastname: Qin
authors.affiliation: Centre for Cancer Research, The University of Hong Kong, Pokfulam, China.|Department of Clinical oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
authors.forename: X Y
authors.initials: XY
authors.lastname: Guan
authors.affiliation: College of Life Science and Technology, Jinan University, 601 West Huangpu Blvd., Guangzhou, China.
authors.forename: Q Y
authors.initials: QY
authors.lastname: He
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.|Centre for Cancer Research, The University of Hong Kong, Pokfulam, China.
authors.forename: A L M
authors.initials: ALM
authors.lastname: Cheung
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D004938:Esophageal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D000071916:AC133 Antigen; C534063:MIRN377 microRNA, human; D035683:MicroRNAs; C000606023:PROM1 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A