Elsevier

Biochimie

Volume 154, November 2018, Pages 119-126
Biochimie

Research paper
miR-487a promotes progression of gastric cancer by targeting TIA1

https://doi.org/10.1016/j.biochi.2018.08.006Get rights and content

Highlights

  • We revealed the biological significance of miR-487a and TIA1 in gastric cancer.

  • TIA1 inhibits cell proliferation and promotes cell apoptosis.

  • miR-487a directly regulates TIA1 through binding to its 3′-untranslated region.

  • miR-487a promotes cell proliferation and inhibits cell apoptosis via targeting TIA1.

  • miR-487a and TIA1 are promising therapeutic targets for gastric cancer treatment.

Abstract

Gastric cancer (GC) is one of the most common malignancies as well as the third leading cause for cancer-related death. Molecular basis of GC are essential and critical for its therapeutic treatment, but still remain poorly understood. T-cell intracellular antigen-1 (TIA1) extensively involves in cancer progression, whereas its role and regulation mechanism in GC have not been revealed. In the present study, we found that TIA-1 protein level was down-regulated in GC tissues and TIA1 inhibited proliferation and promoted apoptosis of GC cells. Then, we used bioinformatics to predict miR-487a as the upstream regulator of TIA1 and we also observed an inverse correlation between miR-487a level and TIA-1 protein level in GC tissues. Next, we demonstrated that miR-487a directly targeted TIA1 via binding to its 3′-untranslated region. Furthermore, we investigated the role of miR-487a-TIA1 pathway in the growth of GC cells both in vitro and in vivo. The repression of TIA-1 by miR-487a promoted cell proliferation and suppressed cell apoptosis in vitro, and the knockdown of miR-487a had the opposite effects. Finally, we demonstrated that miR-487a promoted the development of gastric tumor growth in xenograft mice by targeting TIA-1. These effects could be partially reversed by restoring the expression of TIA-1. Overall, our results reveal that TIA1 is a tumor suppressor gene and is directly regulated by miR-487a in GC, which may offer new therapeutic targets for GC treatment.

Introduction

Gastric cancer (GC) is one of the most common malignant tumors and also one of the most lethal cancer in the worldwide [1,2]. In China, although the incidence has declined in recent years, GC is still the third most common cancer and the third leading cause of cancer-related death [3], which raises a serious threat to public health. Even though the diagnosis and treatment of GC are progressing in recent years, the early diagnosis and overall prognosis are still unsatisfactory [4]. The molecular mechanisms underlying GC, which may provide novel and practical strategies to treat GC as well as to improve the survival rate and life quality of GC patients, remain largely elusive. Therefore, it is still urgently needed to understand the molecular basis of GC and find new therapeutic targets for GC treatment.

T-cell intracellular antigen-1 (TIA1), an RNA-binding protein, is previously well known as a regulator of cellular RNA metabolism and also a key player in human physiology and pathology [[5], [6], [7], [8]]. Recently, more attention has been paid to the dual role of TIA1 in cancer development. In esophageal squamous cell carcinoma (ESCC), TIA1 is found to be overexpressed in ESCC tissues and to promote ESCC cell proliferation [9]. In colorectal carcinoma (CRC), a splice variant of TIA1(sTIA1), a truncated protein, is overexpressed in CRC tissues and increases with tumor stages, and sTIA1 can promote CRC development through regulating vascular endothelial growth factor (VEGF) expression [10]. TIA1 is also overexpressed in hepatocellular carcinoma (HCC) and can down-regulate tumor-suppressing insulin-like growth factor binding protein-3 (IGFBP-3), indicating its potential as therapeutic target for HCC treatment [11,12]. In contrast, some recent studies also reveal TIA1 as a tumor suppressor gene in the progression of various cancers. For example, TIA1 is identified as a tumor suppressor in CRC and regulated by microRNA (miRNA) to promote CRC development [13]. The depletion of TIA1 in ovarian cancer HeLa cells promotes cell proliferation and tumor growth [14,15], and overexpression of TIA1 in lung squamous cell carcinoma (LSCC) results in reduced cell proliferation via selective up-regulation of p53 signaling pathway-related genes [16]. These previous evidences suggest that TIA1 is extensively involved in cancer progression. Meanwhile, the contradictory roles of TIA1 in different cancers indicate that it may be regulated by diverse pathological factors. However, the role of TIA1 in GC is still unknown.

miRNAs are endogenous non-coding RNAs, with the length of 19–23 nucleotides. miRNAs mainly function in negatively regulating gene expression by binding to the 3′-untranslated regions (3′-UTRs) of their target mRNAs, leading to repression of mRNA translation or mRNA decay [17]. It has been estimated that over 50% of human genes are under the regulation by miRNAs [18], suggesting that they are extensively involved in not only normal physiologies but also pathologies. The aberrant expression or function of many miRNAs have been found to be closely related with cancer development [[19], [20], [21], [22]]. miR-487a is initially identified in human fetal liver [23] and contributes to the development of type 1 diabetes [24]. Recently, research on miR-487a has also been expanded into the field of cancer. miR-487a is found to be overexpressed in clear cell renal cell carcinoma (ccRCC) [25], lung cancer [26], breast cancer [27], and HCC [28]. The overexpression of miR-487a promotes cancer progression. Nevertheless, the role of miR-487a in GC and the molecular mechanism through which miR-487a affects GC progression still remain to be elucidated.

In this study, we found that TIA1 was down-regulated in GC and was a tumor suppressor gene in GC. The disagreements between the protein and mRNA expression levels of TIA1 in GC led to the discovery of miR-487a as the post-transcriptional regulator of TIA1. Then, we experimentally confirmed TIA1 as a direct target gene of miR-487a and validated that miR-487a could target TIA1 to promote the growth of GC cells in vitro and in vivo.

Section snippets

Human tissues and cells

The human GC tissues and adjacent noncancerous tissues were acquired from patients undergoing a surgery at the Affiliated Hospital of Zunyi Medical University (Zunyi, China). All protocols about the use of patient samples were approved by the Medical Ethics Committee of the Affiliated Hospital of Zunyi Medical University (Zunyi, China). The tissue samples were immediately freezed in liquid nitrogen at the time of surgery and stored at −80 °C.

The human GC line AGS cells were purchased from the

Down-regulation of TIA1 protein level but not mRNA level in GC tissues

To investigate the role of TIA1 in GC, we first measured the expression levels of TIA1 in GC tissues. 8 pairs of GC tissues and adjacent noncancerous (AN) tissues were used. As shown in Fig. 1a and b, in comparison with that in AN tissues, the protein expression levels of TIA1 in GC tissues were significantly down-regulated. We also measured the mRNA levels of TIA1 in the same 8 pairs of AN and GC tissues. However, no significant difference between TIA1 mRNA levels in cancerous tissues and that

Discussion and conclusion

Since GC patients at the early stages usually have no symptoms, many patients are diagnosed with advanced GC when they went to hospital to seek help for stomach problems. GC is thus among the top leading causes of cancer-related death. For those GC patients whose tumor is inoperable, chemotherapy is a usually used treatment. Recently, increasing attention has been paid to molecular targeted therapy, which specifically targets endogenous molecular targets. TIA1 that is an RNA-binding protein is

Conflicts of interest

The authors declare no conflict of interest.

Author contributions

SYY designed the experiment. XFY, MDW, BHL, DJY, JL, XCT, SHL, YL and RX performed the experiments and data analysis. SYY and XFY wrote the manuscript.

Funding

This research was funded by Science and Technology Foundation of Guizhou Province (Word J [2014] 2185).

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