MiR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGF\u03b2-mediated epithelial to mesenchymal transition

Senlin Zhao,Meng Zhang,Yugang Wen,Xiaofeng Sun,Zongguang Zhou,Xisheng Liu,Weiyingqi Cui,Yushuai Mi,Dongyuan Zhang,Hongcheng Sun,Dongwang Yan,Zhihai Peng,Weiliang Jiang,Yang Yu,Dantong Cheng,Huamei Tang,Shaohan Wu

doi:10.1186/s12943-017-0585-z

Abstract

BackgroundDespite 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.MethodsqPCR 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.ResultsmiR-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.ConclusionmiR-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.

Highlights

Despite advancements in the diagnosis and treatment of colorectal cancer (CRC), many patients die because of tumor metastasis or recurrence
Elevated miR-4775 is correlated with CRC progression and indicates poor survival for CRC patients To investigate the role of miR-4775 in CRC progression, we performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) on 544 pairs of paraffin-embedded normal and CRC tissues
We found that miR-4775 was significantly upregulated in CRC tissues compared to normal tissues (Fig. 1a and e2)

Summary

Introduction

Despite advancements in the diagnosis and treatment of colorectal cancer (CRC), many patients die because of tumor metastasis or recurrence. 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. Many mechanisms underlying these processes have been elucidated and treatment has improved, 50% of CRC patients still develop metastases following surgery [4]. Identification of new predictive markers and the mechanisms involved in the invasion and metastasis of CRC is urgently needed. There are no reports to date on the function of miR-4755 in CRC progression

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