BackgroundIncreasing studies indicated that circRNAs play critical roles in tumor progression. However, the roles and underlying mechanisms of circRNAs in gastric cancer (GC) remain largely unclear.MethodsMicroarray assay was used to screen the abnormally expressed circRNAs in GC. Cell viability assay, transwell assay and in vivo assay were performed to assess the effects of hsa_circ_0081143 on GC cells. Next, interaction between hsa_circ_0081143 and miR-646 was detected by luciferase reporter assay and RNA pull-down assay.ResultsHigh throughput microarray assay showed that hsa_circ_0081143 was upregulated in GC tissues, which was further confirmed by qRT-PCR. Correlation analysis showed that high hsa_circ_0081143 expression was associated with the advanced TNM stage, lymphnode metastases, and poor overall survival of GC patients. Hsa_circ_0081143 inhibition decreased GC cells viability, invasion ability and induced the sensitivity of GC cells to cisplatin (DDP) in vitro. Mechanistically, we showed that hsa_circ_0081143 could act as an endogenous sponge by directly binding to miR-646 and downregulation of miR-646 efficiently reversed the inhibition of CDK6 induced by hsa_circ_008114 knockdown. Additionally, hsa_circ_0081143 silencing suppressed the tumorigenesis and remarkably enhance DDP inhibitory effects of GC cells in vivo.ConclusionsOur study indicated a novel regulatory loop that hsa_circ_0081143/miR-646/CDK6 axis in GC progression. These data suggested that hsa_circ_0081143 might act as a potential novel therapeutic strategy for GC treatment.

Cisplatin resistance in colorectal cancer largely results from the colorectal cancer stem cells which could be targeted to improve the efficacy of chemotherapy. MicroRNAs are possible modulators of cancer stem cell characteristics and maybe involved in the retention of cancer stem cell chemoresistance. The aim of this study was to investigate the biological function of miR-199a/b on cisplatin resistance in colorectal cancer stem cells and its related mechanisms. Here, ALDHA1 cells from primary colorectal cancer tissues behaved similar to cancer stem cells and were chemoresistant to cisplatin. The presence of a variable fraction of ALDHA1 was detected in 9 out of 10 colorectal cancer specimens. Significantly, increased miR-199a/b expression was detected in ALDHA1 colorectal cancer stem cells, accompanied by a downregulation of Gsk3β and an overexpression of β-catenin and ABCG2. In patient cohort, enhanced miR-199a/b expression in colorectal cancer tissues was associated with cisplatin response and poor patient survival. In addition, 80% of colorectal cancer samples showed lower level of Gsk3β than their adjacent normal counterparts. Furthermore, Gsk3β was the direct target of miR-199a/b. MiR-199a/b regulated Wnt/β-catenin pathway by targeting Gsk3β in ALDHA1 colorectal cancer stem cells. By blocking Wnt/β-catenin pathway, we implied that ABCG2 lies downstream of Wnt/β-catenin pathway. ABCG2 was further demonstrated to contribute cisplatin resistance in ALDHA1 colorectal cancer stem cells and can be regulated by miR-199a/b. Thus, our data suggested that upregulation of miR-199a/b in ALDHA1 colorectal cancer stem cells contributed to cisplatin resistance via Wnt/β-catenin-ABCG2 signaling, which sheds new light on understanding the mechanism of cisplatin resistance in colorectal cancer stem cells and facilitates the development of potential therapeutics against colorectal cancer.

Our study shows that miR-367 is a key negative regulator of the invasion and metastasis of gastric cancer and establishes a strong rationale for developing miR-367 as a novel therapeutic agent against gastric cancer.

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