Lithocholic Acid Induces miR21, Promoting PTEN Inhibition via STAT3 and ERK-1/2 Signaling in Colorectal Cancer Cells.

Sun-Young Park,Thuan-Trong Ung,Shinan Li,Sen Lian,Thinh-Thi Nguyen,Dhiraj Kumar Sah,Young-Do Jung

doi:10.3390/ijms221910209

Abstract

Micro-RNA-21 (miR-21) is a vital regulator of colorectal cancer (CRC) progression and has emerged as a potential therapeutic target in CRC treatment. Our study using real-time PCR assay found that a secondary bile acid, lithocholic acid (LCA), stimulated the expression of miR21 in the CRC cell lines. Promoter activity assay showed that LCA strongly stimulated miR21 promoter activity in HCT116 cells in a time- and dose-dependent manner. Studies of chemical inhibitors and miR21 promoter mutants indicated that Erk1/2 signaling, AP-1 transcription factor, and STAT3 are major signals involved in the mechanism of LCA-induced miR21 in HCT116 cells. The elevation of miR21 expression was upstream of the phosphatase and tensin homolog (PTEN) inhibition, and CRC cell proliferation enhancement that was shown to be possibly mediated by PI3K/AKT signaling activation. This study is the first to report that LCA affects miR21 expression in CRC cells, providing us with a better understanding of the cancer-promoting mechanism of bile acids that have been described as the very first promoters of CRC progression.

Highlights

The results show that secondary Bile acids (BAs) significantly induce the expression of miR21 in HCT116 cells, and lithocholic acid (LCA) shows a stronger stimulatory effect on miR21 expression compared to that of deoxycholic acid (DCA), even showing a competitive effect compared to that with PMA, a strong tumor promoter (Figure 1A,B)
A STAT3-activator, interleukin-6, inhibited LCA-induced miR21 expression in a concentration-dependent manner (Figure S4B). These results suggest that STAT3 signal is involved in LCA-induced miR21 expression in HCT116 cells
The study showed that miR21 expression of gastric cancer cells increases when cells are treated with DCA, leading to SOX2 expression suppression and the simultaneous induction of CDX2 expression under BA treatment [16]

Summary

Introduction

Micro-RNA-21 (miR-21) is an abundantly expressed microRNA across various mammalian cells [1,2] and is one of the earliest identified cancer-promoting “oncomiRs”. The carcinogenesis mechanism of miR-21 has been documented to target numerous tumor suppressor genes, including PTEN, PDCD4, TIMP3, and RHOB, which are associated with cell proliferation, migration, invasion, metastasis, and apoptosis [3], or are known to play important roles in signaling pathways such as the RAS/MEK/ERK, PTEN/PI3K/AKT, and Wnt/β-catenin pathways [4]. In a large-scale profiling of miRNA expression in 540 human samples derived from 363 specimens representing six types of solid tumors and 177 respective normal control tissues, miR-21 was the only miRNA upregulated in all analyzed tumors types, including colorectal carcinoma [2]. More recent studies have indicated that miR-21 is upregulated in leukemic cancers [5]

Methods

Results

Conclusion