Oncotarget. 2016 Mar 8;7(10):11364-79 

Human telomerase reverse transcriptase (hTERT) promotes gastric cancer invasion through cooperating with c-Myc to upregulate heparanase expression

Shi-Ming Yang


摘要:

Human telomerase reverse transcriptase (hTERT) is a central regulator of multiple hallmarks of tumors. However, the potential roles of hTERT in tumor invasion and metastasis and the underlying molecular mechanisms remain poorly understood. Here, we found that the expression of hTERT in gastric cancer (GC) was significantly associated with an advanced TNM stage, lymphatic metastasis. Survival analysis identified hTERT as an independent prognostic factor for survival of GC patients. hTERT promoted the invasion and metastasis of GC cells by binding to c-Myc and recruiting the complex to heparanase promoter to upregulate heparanase expression. In addition, our data demonstrated that hTERT activated Wnt/β-catenin signaling to promote c-Myc expression which could in turn activate hTERT transcription and expression, suggesting a positive feedback regulation in GC progression. Consistently, c-Myc and heparanase expression was positively correlated with hTERT levels, and was also an independent predictor of metastasis and survival. Collectively, our data provide a novel molecular mechanism for hTERT in promotion of GC invasion and metastasis, and highlight the molecular etiology and clinical significance of hTERT in GC progression. Targeting hTERT may represent a new therapeutic strategy to improve therapy and survival of GC patients.Our previous studies have demonstrated that the expression of hTERT is associated with the proliferation and tumorigenesis of GC [22, 23]. We then compared the expression levels of hTERT and heparanase in GC cell lines, and found that hTERT and heparanase were expressed relatively higher in MKN45 cells while lower in SGC7901 cells (Supplementary Figure S1A). We selected these two cell lines in the following experiments. Consistent with the previous studies [24], overexpression of hTERT enhanced the invasion of GC cells, whereas knockdown of hTERT significantly inhibited the invasion in vitro (Supplementary Figure S1B and S1C). Stable GC cell lines were established and the protein expression was confirmed (Supplementary Figure S2A). Pulmonary metastasis and peritoneal dissemination assays were performed to test the metastasis of GC cells in vivo. Overexpression of hTERT increased the number of metastasis nodules in the lung and peritoneal cavity, while hTERT-knockdown repressed pulmonary metastasis and peritoneal dissemination in vivo (Supplementary Figure S2B and S2C).Since heparanase (Hpa) played a key role in invasion and metastasis of cancer cells [15–17], we then tested the expression levels of hTERT and Hpa by immunohistochemical assays (Figure 1A). The expression levels of hTERT and Hpa were clearly higher in GC tissues than those in adjacent normal tissues (Figure 1B and 1C). Furthermore, we found that hTERT expression was positively correlated with Hpa expression in GC tissues (Figure 1D). Taken together, hTERT could promote the invasion and metastasis of GC cells in vitro and in vivo, and the expression of hTERT was positively correlated with Hpa expression in GC tissues.The study was approved by the Clinical Research Ethics Committee of the Third Military Medical University. Informed consent was obtained from each patient. All of the animal experimental procedures were performed according to the “Guide for the Care and Use of Laboratory Animals” published by National Institutes of Health and Ethics Committee of the Third Military Medical University.We thank Su-Min Wang and Yu-Yun Wu for their assistance in tissue collection and animal study, and Wei Sun (Central Laboratory, Third Military Medical University, Chongqing, China) for technical assistance.CONFLICTS OF INTERESTThe authors declare to have no conflict of interests.GRANT SUPPORTThis work was supported by National Natural Science Foundation of China (No. 81272689).
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