Original ArticleLong non-coding RNA HNF1A-AS1 mediated repression of miR-34a/SIRT1/p53 feedback loop promotes the metastatic progression of colon cancer by functioning as a competing endogenous RNA
Introduction
Colon cancer ranks as the third most prevalent type of malignancy and accounts for one-tenth of all cancer-related death in both men and women [1]. In China, more than 376,300 new cases (including rectum cancer) and 191,000 deaths occurred in 2015 [2]. Although the advances in surgical techniques and adjuvant chemo/radio-therapies have been made, the prognosis of patients with advanced stage remains frustrating and the 5-year survival rate is in relative low level due to frequent recurrence and metastasis [3]. Furthermore, the underlying molecular mechanism of colon cancer is not fully understood despite its commonness with other cancers. Consequently, there is a compelling need for better understanding of colon cancer mechanism, in expecting to improve effectiveness of therapy and overall prognosis.
Recently, many long noncoding RNAs (lncRNAs) are shown to regulate important cancer hallmarks, including proliferation, apoptosis, metastasis, senescence, self-renewal, stem cell pluripotency and drug-resistance [4], [5], [6], [7], [8], [9]. This largest novel heterogeneous class of noncoding RNAs (ncRNAs), which range from 200 nucleotides to multiple kilobases in length, accounts for much of the transcribed genome [10], [11], and gains widespread and sustained concern. Nevertheless, the clinical relevance of lncRNAs in colon cancer remains largely unexplored. A newly identified long non-coding RNA HNF1A-AS1 (HNF1A antisense RNA 1), which transcribed from the opposite strand of HNF1A gene transcription is a 2455-nucleotide single-exon transcript with no protein-coding capacity located at chromosomal band 12q24.31 [12], [13], [14]. A previous report demonstrated that lncRNA HNF1A-AS1 was detectable and highly expressed in human gastrointestinal track including esophagus, small intestine and colon by expression profiling of HNF1A-AS1 across 20 normal human tissues [13]. Dysregulation of HNF1A-AS1 has been reported in esophageal adenocarcinoma, gastric cancer and many other types of human cancers, and studies on HNF1A-AS1 function in cancers exert both oncogenic and tumor suppressive effects [13], [14], [15], [16], [17]. The reported HNF1A-AS1 activities are diverse, including modulation of chromatin and nucleosome assembly, mutual regulation between two cancer-related lncRNAs by induction of H19 [13], interaction with epigenetic regulators [14], [17], regulation of microRNAs as competing endogenous RNA (ceRNA) [15]. However, the functional role and underlying molecular mechanism of HNF1A-AS1 in colon cancer has not been investigated. These prompted us to explore the role of HNF1A-AS1 in human colon cancer.
In the present study, we performed in vitro and in vivo experiments to investigate HNF1A-AS1 activity and possible mechanism in colon cancer. We found that HNF1A-AS1 was upregulated in colon cancer tissues, where it was significantly correlated with advanced stage, vascular invasion, lymph node and distant metastasis. HNF1A-AS1 silencing decreased colon cancer cell proliferation and invasion and increased apoptosis. Moreover, HNF1A-AS1 promotes the progression of colon cancer by functioning as a competing endogenous RNA to modulate miRNA-34a expression, consequently with repression of miR-34a/SIRT1/p53 feedback loop and activation of canonical Wnt signaling pathway. Our results shed new light on the prospect for manipulating HNF1A-AS1 expression as a potential novel therapeutic approach to anti-cancer therapy of colon cancer as well as a new prognostic biomarker.
Section snippets
Tissue samples collection and cell lines culture
Ninety-eight paired colon cancer tissues and adjacent normal tissues were obtained from patients who underwent surgery at Shanghai General Hospital between August 2009 and September 2011. All specimens were histopathologically confirmed and obtained with informed consent. No patient received preoperative local or systemic anticancer treatment. Tumor stage was classified according to the guidelines of the 7th Edition of the AJCC (American Joint Committee on Cancer) Cancer Staging Manual of TNM.
Upregulation of HNF1A-AS1 is correlated with unfavorable prognosis in colon cancer
Quantitative real-time PCR analysis was conducted to detect HNF1A-AS1 expression pattern in 98 paired clinical colon cancer tissue samples. HNF1A-AS1 expression was significantly upregulated in most tumor tissues (66/98, 67.3%) compared with the adjacent normal counterparts (Fig. 1A). In addition, to investigate the clinical significance of HNF1A-AS1, the correlations between its expression level and clinicopathological characteristics were analyzed. The analysis results showed that HNF1A-AS1
Discussion
This report is the first direct investigation of the expression pattern and clinical relevance of lncRNAHNF1A-AS1 in colon cancer. In this report, we found that HNF1A-AS1 was frequently upregulated in colon cancer tissues and associated with poor prognosis. Upregulated HNF1A-AS1 promoted colon cancer cell viability, migration and invasion both in vitro and in vivo. Mechanistically, HNF1A-AS1 promoted metastatic progression by inhibiting colon cancer cell apoptosis via involvement in the
Conclusions
In summary, the study illustrates that lncRNA HNF1A-AS1 functions as an oncogene to facilitate colon cancer cell proliferation, invasion and metastasis in a miR-34a/p53 -dependent manner. Our results shed new light on the prospect for manipulating HNF1A-AS1 expression as a potential novel therapeutic approach to anti-cancer therapy of colon cancer as well as a novel prognostic biomarker.
Acknowledgements
This work was supported by grants from Shanghai Municipal Natural Science Foundation (No. 16ZR1427700) and Medical Guidance Project of Shanghai Science and Technology Commission (No. 17411968200).
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- 1
These authors contributed equally to this work.