Long noncoding RNA SNHG16 induces sorafenib resistance in hepatocellular carcinoma cells through sponging miR-140-5p

Abstract

BackgroundSorafenib is widely used for treatment of hepatocellular carcinoma (HCC), but the acquired resistance remains a major obstacle for its application. Thus it is of critical importance to elucidate the molecular mechanisms underlying sorafenib resistance in HCC. This study aimed to determine the roles of long noncoding RNA SNHG16 in sorafenib-resistant HCC cells.MethodsHCC and matched adjacent normal liver tissue samples were obtained from 103 HCC patients. Sorafenib-resistant HepG2/SOR cell line was established from its parental HepG2 cells by exposure to increasing concentrations of sorafenib. SNHG16 and miR-140-5p expression levels in tissue samples and cells were detected by RT-qPCR analysis. The sensitivity of cells to sorafenib in vitro was evaluated by MTT assay, and the sensitivity of HepG2/SOR cells to sorafenib in vivo was estimated using the nude mouse-based xenograft model. The potential binding relation between SNHG16 and miR-140-5p was validated by dual luciferase reporter assay and biotinylated RNA pull-down assay.ResultsThe results showed that SNHG16 expression was remarkably increased in HCC tissues and cell lines, and its high expression was closely associated with aggressive clinicopathological features and poor prognosis of HCC patients. Further experiments showed that SNHG16 is upregulated in HepG2/SOR cells, whereas knockdown of SNHG16 increases the sensitivity of HepG2/SOR cells to sorafenib in vitro and in vivo. Further mechanistic study identified that SNHG16 functions as an endogenous sponge for miR-140-5p in HepG2 cells, and in HCC tissues, the expression of miR-140-5p is negatively correlated with SNHG16 expression. Moreover, miR-140-5p overexpression also increases the sensitivity of HepG2/SOR cells to sorafenib, and the effects of SNHG16 knockdown on sorafenib resistance could be blocked by miR-140-5p inhibitor.ConclusionCollectively, our findings demonstrated that knockdown of SNHG16 attenuated sorafenib resistance in HCC through sponging miR-140-5p, indicating that SNHG16 might be as a promising therapeutic target to boost the effectiveness of chemotherapy for HCC patients.

Clinicopathological significance and prognosis of long noncoding RNA SNHG16 expression in human cancers: a meta-analysis

“…Research conducted by Cao et al indicated that SNHG16 was a poor prognostic marker, which can promote tumor proliferation by epigenetically silencing p21 in bladder cancer [10]. Meanwhile, SNHG16 contributes to sorafenib resistance by sponging miR-140-5p in hepatocellular carcinoma [17]. Christensen et al found that SNHG16 was upregulated in colorectal cancer by affecting lipid metabolism [9].…”

“…Some studies have revealed that upregulated SNHG16 expression predicted poor prognosis for some cancers [26]. Moreover, the expression level of SNHG16 is closely related to TNM stage, distant metastasis, lymph node metastasis, overall survival (OS), and other clinical attributes [17]. Therefore, we conducted a meta-analysis to investigate whether the lncRNA SNHG16 can be used as a prognostic biomarker for human cancers.…”

<p><em>SNHG16</em>: A Novel Long-Non Coding RNA in Human Cancers</p>

“…The expression of SNHG16 is also remarkably upregulated in HCC cell lines. 15,[18][19][20][21][22][23] Further analysis showed that high expression of SNHG16 is associated with high tumor grade, multiple tumors, macrovascular invasion, large tumor size, and lymph node status, as well as poor diseasefree survival and shorter overall survival. 15,[19][20][21]23 In HCC patients, multivariate analysis identified SNHG16 overexpression as a significant independent predictor of poor prognosis.…”

“…Ye et al and Guo et al both found that knocking down SNHG16 increased sensitivity to sorafenib in HCC cells via acting as an endogenous sponge for miR-140-5p, which indicates that SNHG16 might be a promising therapeutic target to boost the effectiveness of chemotherapy for HCC patients. 18,23 Osteosarcoma is a rare cancerous bone tumor characterized by high metastasis, rapid progression, and poor prognosis. 67 In the past few decades, there has been great progress in the diagnosis and treatment of osteosarcoma, but the OS is still unsatisfactory.…”

“…17 Recent studies have demonstrated that SNHG16 expression is upregulated in multiple types of tumors. Furthermore, downregulation of SNHG16 in cancer cells inhibits cell proliferation, invasion, and migration; induces apoptosis; and results in decreased N-cadherin and increased E-cadherin, 15,[18][19][20][21][22][23] suggesting that SNHG16 also acts as an oncogenic lncRNA in cancer.…”