ANRIL promotes chemoresistance via disturbing expression of ABCC1 by regulating the expression of Let-7a in colorectal cancer.

Zhen Zhang,Pengfei Liu,Lifeng Feng,Wei Duan

doi:10.1042/bsr20180620

Abstract

Increasing evidence indicates that long non-coding RNAs (lncRNAs) antisense non-coding RNA in the INK4 locus (ANRIL) has been involved in various diseases and promotes tumorigenesis and cancer progression as an oncogenic gene. However, the effect of ANRIL on chemoresistance remains still unknown in colorectal cancer (CRC). Here, we investigated ANRIL expression in 63 cases of colorectal cancer specimens and matched normal tissues. Results revealed that ANRIL was up-regulated in tumor tissues samples from patients with CRC and CRC cell lines. Increased ANRIL expression in CRC was associated with poor clinical prognosis. Kaplan–Meier analysis showed that ANRIL was associated with overall survival of patients with colorectal cancer, and patients with high ANRIL expression tended to have unfavorable outcome. In vitro experiments revealed that ANRIL knockdown significantly inhibited CRC cell proliferation, improved the sensitivity of chemotherapy and promoted apoptosis. Further functional assays indicated that ANRIL overexpression significantly promoted cell chemoresistance by regulating ATP-binding cassette subfamily C member 1 through binding Let-7a. Taken together, our study demonstrates that ANRIL could act as a functional oncogene in CRC, as well as a potential therapeutic target to inhibit CRC chemoresistance.

Highlights

Colorectal cancer (CRC) is the third most common human cancer and the fourth most common cause of cancer deaths in global and its incidence has increased in recent years [1]
We found antisense non-coding RNA in the INK4 locus (ANRIL) expression was correlated with disease stage, the expression of ANRIL was higher in patients with advanced stage or with lymph node metastasis (LNM) compared with patients with stage I-II or without LNM (Figure 1E,F)
We found that the ANRIL expression level was much higher in patients who did not respond to treatment than those who experienced response to chemotherapy (Figure 1G)

Summary

Introduction

Colorectal cancer (CRC) is the third most common human cancer and the fourth most common cause of cancer deaths in global and its incidence has increased in recent years [1]. Encouraging advances in diagnosis and cancer therapy in the past decade, CRC remains a high-risk digestive tract tumor with the low overall survival rate due to CRC metastasis and chemoresistance. The prognosis and treatment strategies of CRC rely on tumor stage [2]. Despite receiving standard chemotherapy regimens, most of CRC patients eventually generate chemoresistance and cause to treatment failure [5]. Even though great efforts have spent to explore the cause of CRC tolerance for chemotherapy, the molecular mechanisms of CRC chemoresistance remain unclear.

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Results

Conclusion