Sorafenib resistance remains a major obstacle for the effective treatments of hepatocellular carcinoma (HCC). Recent studies indicate that activated Akt contributes to the acquired resistance to sorafenib, and miR-21 dysregulates phosphatase and tensin homolog (PTEN), which inhibits Akt activation. Sorafenib-resistant HCC cells were shown to be refractory to sorafenib-induced growth inhibition and apoptosis. Akt and its downstream factors were highly activated and/or upregulated in sorafenib-resistant cells. Inhibition of autophagy decreased the sensitivity of sorafenib-resistant cells to sorafenib, while its induction had the opposite effect. Differential screening of miRNAs showed higher levels of miR-21 in sorafenib-resistant HCC cells. Exposure of HCC cells to sorafenib led to an increase in miR-21 expression, a decrease in PTEN expression and sequential Akt activation. Transfection of miR-21 mimics in HCC cells restored sorafenib resistance by inhibiting autophagy. Anti-miR-21 oligonucleotides re-sensitized sorafenib-resistant cells by promoting autophagy. Inhibition of miR-21 enhances the efficacy of sorafenib in treating sorafenib-resistant HCC tumors in vivo. We conclude that miR-21 participates in the acquired resistance of sorafenib by suppresing autophagy through the Akt/PTEN pathway. MiR-21 could serve as a therapeutic target for overcoming sorafenib resistance in the treatment of HCC.

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BackgroundThe detection of serum tumor marker becomes a common method for screening tumors. However, this method has not been widely used for routine gastric cancer screening. In this study we aimed to determine whether the combined use of tumor markers may increase the sensitivity for the diagnosis of gastric cancer.MethodsSerum AFP, CEA, CA125 and CA19-9 levels were measured in 149 patients with gastric cancer, 111 patients with benign gastric diseases and 124 healthy people, who visited the First Affiliated Hospital of Nanchang University from May 2011 to May 2012. Statistical analysis including receiver operating characteristic (ROC) curve, the area under the curve (AUC), and logistic regression analysis was performed to evaluate the diagnostic value of these markers on gastric cancer.ResultsSerum levels of CEA, CA125, and CA19-9 in gastric cancer group were higher than that in the benign gastric disease group and the healthy control group (P <0.005). The sensitivity of AFP, CEA, CA125 and CA19-9 in the diagnosis of gastric cancer was 4.7-20.8% individually, and increased to 40.3% in combination. By using optimal cut-off value, the sensitivity of CEA, CA125, and CA19-9 for the diagnosis of gastric cancer was improved. Especially, the sensitivity of CEA increased to 58.4% and the sensitivity of combined use of four markers increased to 69.1%. The age and gender had no effects on the diagnostic value of these markers.ConclusionsThe determination and application of optimal cut-off values based on ROC curve and logistic regression analysis could improve the diagnosis of gastric cancer based on common tumor markers.

Background Acquired resistance to sorafenib greatly limits its therapeutic efficiency in the treatment of hepatocellular carcinoma (HCC). Increasing evidence indicates that long noncoding RNAs (lncRNAs) play important roles in the resistance to anti-cancer drugs. The present study aims to explore the involvement of lncRNA SNHG1 (small nucleolar RNA host gene 1) in sorafenib resistance and how SNHG1 is associated with overexpressed microRNA-21 (miR-21) and the activated Akt pathway, which have been demonstrated to mediate this resistance in HCC cells. Methods Sorafenib-resistant HCC (SR-HCC) cells were generated and their sorafenib-resistant properties were confirmed by cell viability and apoptosis assays. Potential lncRNAs were screened by using multiple bioinformatics analyses and databases. The expression of genes and proteins was detected by qRT-PCR, Western blot and in situ hybridization. Gene silencing was achieved by specific siRNA or lncRNA Smart Silencer. The effects of anti-SNHG1 were evaluated in vitro and in experimental animals by using quantitative measures of cell proliferation, apoptosis and autophagy. The binding sites of miR-21 and SNHG1 were predicted by using the RNAhybrid algorithm and their interaction was verified by luciferase assays. Results The Akt pathway was highly activated by overexpressed miR-21 in SR-HCC cells compared with parental HCC cells. Among ten screened candidates, SNHG1 showed the largest folds of alteration between SR-HCC and parental cells and between vehicle- and sorafenib-treated cells. Overexpressed SNHG1 contributes to sorafenib resistance by activating the Akt pathway via regulating SLC3A2. Depletion of SNHG1 enhanced the efficacy of sorafenib to induce apoptosis and autophagy of SR-HCC cells by inhibiting the activation of Akt pathway. Sorafenib induced translocation of miR-21 to the nucleus, where it promoted the expression of SNHG1, resulting in upregulation of SLC3A2, leading to the activation of Akt pathway. In contrast, SNHG1 was shown to have little effect on the expression of miR-21, which downregulated the expression of PTEN, leading to the activation of the Akt pathway independently of SNHG1. Conclusions The present study has demonstrated that lncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib. These results indicate that SNHG1 may represent a potentially valuable target for overcoming sorafenib resistance for HCC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1177-0) contains supplementary material, which is available to authorized users.

Background:Phosphatase of regenerating liver-3 (PRL-3) is an oncogene known to promote tumour metastasis, especially in colorectal cancer (CRC). Here, we demonstrate that the miR-21, miR-17 and miR-19a expressions induced by PRL-3 are involved in the proliferation and metastasis of colon cancer.Methods:Microarray analysis and quantitative reverse-transcription polymerase chain reactions (qRT–PCR) were used to investigate the changes in miRNA expression due to the overexpression of PRL-3. Transwell chamber invasion assays, CCK-8 proliferation assays and RNA interference assays were used to explore the effects of PRL-3 on miR-21, miR-17 and miR-19a expression in colon cancer cells. Immunohistochemistry and qRT–PCR were performed in colon cancer tissues to evaluate the expression of PRL-3, signal transducer and activator of transcription 3 (STAT3), miR-21, miR-17 and miR-19a.Results:Our study demonstrated that the overexpression of PRL-3 in colon cancer cells induced the expression of miR-21, miR-17 and miR-19a by activating STAT3. Subsequently, these microRNAs contributed to the increased proliferation and invasiveness of the colon cancer cells. Positive correlations between PRL-3 and these microRNAs were also observed in matched primary colon cancer tissues and metastatic lesions.Conclusion:miR-21, miR-17 and miR-19a induced by PRL-3 contribute to the proliferation and invasion of colon cancer.

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