Methyltransferase-like 1 (METTL1) mediated 7-methylguanosine (m7G) is crucial for the regulation of chemoresistance in cancer treatment. However, the role of METTL1 in regulating chemoresistance of colon cancer (CC) cells to cisplatin is still unclear. This study established the cisplatin-resistant CC (CR-CC) cells and found that METTL1 was low-expressed in CR-CC cells compared to their paired cisplatin-sensitive CC (CS-CC) cells. Besides, overexpressed METTL1 enhanced the cytotoxic effects of cisplatin on CR-CC cells. In addition, miR-149-3p was the downstream target of METTL1, which could be positively regulated by METTL1. Further results validated that miR-149-3p was low-expressed in CR-CC cells comparing to the CS-CC cells. In addition, the promoting effects of overexpressed METTL1 on cisplatin induced CR-CC cell death were abrogated by synergistically knocking down miR-149-3p. Furthermore, S100A4/p53 axis was the downstream target of METTL1 and miR-149-3p, and either overexpressed METTL1 or miR-149-3p increased p53 protein levels in CR-CC cells, which were reversed by upregulating S100A4. Similarly, the promoting effects of overexpressed METTL1 on cisplatin-induced CR-CC cell death were abrogated by overexpressing S100A4. Taken together, overexpression of METTL1 sensitized CR-CC cells to cisplatin by modulating miR-149-3p/S100A4/p53 axis.

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Approximately 9% of cancer-related deaths are caused by colorectal cancer. Liver metastasis is a major factor for the high colorectal cancer mortality rate. However, the molecular mechanism underlying colorectal cancer liver metastasis remains unclear. Using a global and multidimensional integration approach, we studied sequencing data, protein-protein interactions, and regulation of transcription factor and non-coding RNAs in primary tumor samples and liver metastasis samples to unveil the potential bridging molecules and the regulators that functionally link different stages of colorectal cancer liver metastasis. Primary tumor samples and liver metastasis samples had modules with significant overlap and crosstalk from which we identified several bridging genes (e.g. KNG1 and COX5B), transcription factors (e.g. E2F4 and CDX2), microRNAs (e.g. miR-590-3p and miR-203) and lncRNAs (e.g. lincIRX5 and lincFOXF1) that may play an important role in the process of colorectal cancer liver metastasis. This study enhances our understanding of the genetic alterations and transcriptional regulation that drive the metastatic process, but also provides the methodology to guide the studies on other metastatic cancers.

Endogenous transfer RNA‐derived small RNAs (tsRNAs) are newly identified RNAs that are closely associated with the pathogenesis of multiple diseases, but the involvement of tsRNAs in regulating acute pancreatitis (AP) development has not been reported. In this study, we screened out a novel tsRNA, tRF3‐Thr‐AGT, that was aberrantly downregulated in the acinar cell line AR42J treated with sodium taurocholate (STC) and the pancreatic tissues of STC‐induced AP rat models. In addition, STC treatment suppressed cell viability, induced pyroptotic cell death and cellular inflammation in AP models in vitro and in vivo. Overexpression of tRF3‐Thr‐AGT partially reversed STC‐induced detrimental effects on the AR42J cells. Next, Z‐DNA‐binding protein 1 (ZBP1) was identified as the downstream target of tRF3‐Thr‐AGT. Interestingly, upregulation of tRF3‐Thr‐AGT suppressed NOD‐like receptor protein 3 (NLRP3)‐mediated pyroptotic cell death in STC‐treated AR42J cells via degrading ZBP1. Moreover, the effects of tRF3‐Thr‐AGT overexpression on cell viability and inflammation in AR42J cells were abrogated by upregulating ZBP1 and NLRP3. Collectively, our data indicated that tRF3‐Thr‐AGT suppressed ZBP1 expressions to restrain NLRP3‐mediated pyroptotic cell death and inflammation in AP models. This study, for the first time, identified the role and potential underlying mechanisms by which tRF3‐Thr‐AGT regulated AP pathogenesis.

The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing yearly, making it the second most common carcinoma after hepatocellular carcinoma among primary malignant liver tumors. Integrated miRNA and mRNA analysis is becoming more frequently used in antitumor ICC treatment. However, this approach generates vast amounts of data, which leads to difficulties performing comprehensive analyses to identify specific therapeutic drug targets. In this study, we provide an in-depth analysis of ICC function, identifying potential highly potent antitumor drugs for antitumor therapy. Two sets of whole genome expression profiles were obtained from the Gene Expression Omnibus (GEO) database. Using modular bioinformatic analysis, six core functional modules were identified for ICC. Based on a Fisher's test of the Cmap small molecule drug database, 65 drug components were identified that regulated the genes of these six core modules. Literature mining was then used to identify 15 new potential antitumor drugs.