Decreased expression of the long noncoding RNA LINC00261 indicate poor prognosis in gastric cancer and suppress gastric cancer metastasis by affecting the epithelial–mesenchymal transition

Many lncRNAs have been implicated in various types of cancers. Reportedly, the lncRNAs of the class MALAT-1 have been found to promote cell motility in lung adenocarcinoma cells [17]. PCGEM1 overexpression and PRNCR1 have been found to be involved in the development of prostate cancer [18, 19]. Recent findings have also suggested that many lncRNAs have important roles in GC. MALAT1 and HOTAIR were recently reported to drive GC development and promote peritoneal metastasis. Xu et al. revealed that the lncRNA FENDRR inhibits invasive and metastatic behavior in GC cells [10]. TINCR was reported to promote GC proliferation by accelerating KLF2 mRNA degradation [11]. Therefore, the identification of GC-associated lncRNAs may provide a missing piece of the well-known oncogenic and tumor suppressor network puzzle.

Previous profiling study identified that LINC00261 was downregulated in GC tissues compared to normal tissue samples [14]. However, its function in carcinogenesis and tumor progression is unclear. In this study, we confirmed that LINC00261 levels were decreased in GC cells and tissues compared with the normal gastric epithelial cells and adjacent normal tissues. LINC00261 can serve as a biomarker to distinguish cancer tissue with non-tumor tissue in GC. Moreover, low LINC00261 expression was significantly correlated with aggressive tumor characteristics (greater invasion depth, higher tumor stage, and lymphatic metastasis) and poor prognosis. When the patients were subdivided into four groups according to tumor stage, we found that LINC00261 expression could distinguish patients with different outcomes in stages III and IV. However, we did not observe a significant correlation between LINC00261 expression and clinical outcomes in the early clinical stages of GC, probably due to better outcome in the early stage of GC after treatment of operation. Univariate and multivariate analyses indicated that DFS were significantly better among patients with high LINC00261 expression than in patients with low LINC00261 expression in the same stage. Multivariate analysis demonstrated that LINC00261 expression was an independent prognostic factor for GC patients. This suggests that LINC00261 might be a promising prognostic and diagnostic biomarker in GC patients.

As low LINC00261 expression was associated with an aggressive tumor phenotype in GC, we speculated that LINC00261 could play a significant role in tumor biology. Initially, we chose representative cell lines of GC and investigated their LINC00261 expression in comparison to a non-tumoral gastric cell line. We observed that all of the five tumor cell lines exhibited low LINC00261 expression, which corroborated our previous findings. We next determined whether LINC00261 expression influenced tumor-like characteristics, such as proliferation and metastasis. Ectopic expression of LINC00261 inhibited cell migration and invasion, whereas knockdown of endogenous LINC00261 expression significantly enhanced these capacities. Moreover, increased LINC00261 expression significantly reduced the number of metastatic nodules on the lungs in vivo. However, no significant effect on cellular proliferation was observed after ectopic expression or knockdown of LINC00261. This is in line with our clinical findings that LINC00261 was significantly correlated with invasion depth, tumor stage, and lymphatic metastasis, but not tumor size. These results revealed that LINC00261 might impact the prognosis of GC by affecting cell migration and invasion.

To explore the molecular mechanism through which LINC00261 contributes to invasion and metastasis in GC, we investigated potential target proteins involved in cell motility and matrix invasion. The EMT plays crucial roles during cancer initiation and progression, especially in cancer metastasis [20–22]. Previous data has been revealed that lncRNAs regulate tumor cell metastasis by affecting the EMT process [23, 24]. Hallmarks of EMT are the loss of E-cadherin expression and the aberrant expression of N-cadherin and Vimentin. Therefore, we determined the levels of these EMT-induced markers following overexpression or inhibition of LINC00261. Our results indicated that LINC00261 mediated inhibitory effects on GC cell metastasis suppression, possibly by affecting the EMT. As a central differentiation process, EMT allows for the remodeling of tissues during the early stages of embryogenesis and is implicated in the promotion of tumor cell invasion and metastasis. Therefore, as regulators of EMT, lncRNAs could be suitable candidates for intervention in the treatment of cancer. In recent years, molecularly targeted therapeutics for key molecular drivers of cancer progression has been developed [25]. LINC00261, as an important regulator of EMT, promise to serve as a drug target. Drugs which could regulate the expression of LINC00261 have clinical application prospects, so clinical test or assay could be developed to test these.