title: miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFβ-mediated epithelial to mesenchymal transition.
abstract: Despite advancements in the diagnosis and treatment of colorectal cancer (CRC), many patients die because of tumor metastasis or recurrence. Therefore, identifying new prognostic markers and elucidating the mechanisms of CRC metastasis and recurrence will help to improve the prognosis of the disease. As dysregulation of microRNAs is strongly related to cancer progression, the aim of this study was to identify the role of miR-4775 in the prognosis of CRC patients and the underling mechanisms involved in CRC progression.
  
  
  
  qPCR and in situ hybridization were used to evaluate the expression of miR-4775 in 544 pairs of paraffin-embedded normal and CRC tissues. Kaplan-Meier analysis with the log-rank test was used for survival analyses. Immunohistochemical staining was applied to investigate the expression of miR-4775-regulated Smad7/TGFβ pathway-associated markers. In vitro and in vivo invasion and metastasis assays were used to explore the function of miR-4775 in the progression of CRC.
  
  
  
  miR-4775 was identified as a high-risk factor for CRC metastasis and recurrence, with high levels predicting poor survival among the 544 studied CRC patients. Furthermore, high miR-4775 expression promoted the invasion of CRC cells as well as metastasis and the epithelial to mesenchymal transition (EMT) via Smad7-mediated activation of TGFβ signaling both in vitro and in vivo. Downregulating miR-4775 or overexpressing Smad7 reversed the tumor-promoting roles of miR-4775/Smad7/TGFβ in vitro and in vivo.
  
  
  
  miR-4775 promotes CRC metastasis and recurrence in a Smad7/TGFβ signaling-dependent manner, providing a new therapeutic target for inhibiting the metastasis or recurrence of the disease.
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Senlin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Hongcheng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Yushuai
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Dongyuan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Dantong
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Huamei
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Jiaxing College, 1518 Huancheng North Road, Jiaxing, Zhejiang, 314000, China.
authors.forename: Shaohan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, SE-581 83, Linköping, Sweden.
authors.forename: Weiyingqi
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Pathology, Fudan University, Shanghai Cancer Center, 270 Dongan Road, 200030, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, SE-581 83, Linköping, Sweden.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang Street, Chengdu, 610041, Sichuan, China.
authors.forename: Zongguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China. pengpzhh@hotmail.com.
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China. yandw70@163.com.
authors.forename: Dongwang
authors.initials: D
authors.lastname: Yan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta
keywords: Colorectal cancer; EMT; Smad7; TGFβ signaling; miR-4775