Mis-regulated epigenetic modifications in RNAs are associated with human cancers. The transfer RNAs (tRNAs) are the most heavily modified RNA species in cells; however, little is known about the functions of tRNA modifications in cancers. In this study, we uncovered that the expression levels of tRNA N⁷-methylguanosine (m⁷G) methyltransferase complex components methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) are significantly elevated in human lung cancer samples and negatively associated with patient prognosis. Impaired m⁷G tRNA modification upon METTL1/WDR4 depletion resulted in decreased cell proliferation, colony formation, cell invasion, and impaired tumorigenic capacities of lung cancer cells in vitro and in vivo. Moreover, gain-of-function and mutagenesis experiments revealed that METTL1 promoted lung cancer growth and invasion through regulation of m⁷G tRNA modifications. Profiling of tRNA methylation and mRNA translation revealed that highly translated mRNAs have higher frequencies of m⁷G tRNA-decoded codons, and knockdown of METTL1 resulted in decreased translation of mRNAs with higher frequencies of m⁷G tRNA codons, suggesting that tRNA modifications and codon usage play an essential function in mRNA translation regulation. Our data uncovered novel insights on mRNA translation regulation through tRNA modifications and the corresponding mRNA codon compositions in lung cancer, providing a new molecular basis underlying lung cancer progression.

According to cancer-related microRNA (miRNA) expression microarray research available in public databases, miR-362 expression is elevated in gastric cancer. However, the expression and biological role of miR-362 in gastric progression remain unclear.

Macrophage migration inhibitory factor (MIF), a proinflammatory and immunoregulatory chemokine, plays important roles in cancer-related biological processes. However, few studies have focused on the clinical relevance of MIF and cyclin D1 expression in hepatocellular carcinoma cells (HCCs). In this study, MIF and cyclin D1 expression levels in HCC tissues and cell lines were significantly upregulated compared with adjacent normal tissues or a normal liver cell line. In HCC specimens, MIF expression positively correlated with cyclin D1 expression. Additionally, MIF and cyclin D1 expression positively correlated with tumor size. MIF knockdown inhibited the proliferation of PLC and HepG2 cells and promoted apoptosis. However, small interfering RNA (siRNA) against MIF did not influence the cell cycle in these cells. In an in vivo xenograft model, MIF knockdown reduced the tumor growth rate. The expression levels of p-caspase-3, BIM and Bax were upregulated, while the expression levels of cyclin D1, p-Akt and p-ERK were downregulated in MIF-knockdown cells. These findings indicate that MIF siRNA reduces proliferation and increases apoptosis in HCC cells. MIF knockdown inhibits the expression of growth-related proteins and induces the expression of apoptosis-related proteins, supporting a role for MIF as a novel therapeutic target for HCC.

Aberrant A‐to‐I RNA editing, mediated by ADAR1 has been found to be associated with increased tumourigenesis and the development of chemotherapy resistance in various types of cancer. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with a poor prognosis, and overcoming chemotherapy resistance poses a significant clinical challenge. This study aimed to clarify the roles of ADAR1 in tumour resistance to cisplatin in iCCA. We discovered that ADAR1 expression is elevated in iCCA patients, particularly in those resistant to cisplatin, and associated with poor clinical outcomes. Downregulation of ADAR1 can increase the sensitivity of iCCA cells to cisplatin treatment, whereas its overexpression has the inverse effect. By integrating RNA sequencing and Sanger sequencing, we identified BRCA2, a critical DNA damage repair gene, as a downstream target of ADAR1 in iCCA. ADAR1 mediates the A‐to‐I editing in BRCA2 3′UTR, inhibiting miR‐3157‐5p binding, consequently increasing BRCA2 mRNA and protein levels. Furthermore, ADAR1 enhances cellular DNA damage repair ability and facilitates cisplatin resistance in iCCA cells. Combining ADAR1 targeting with cisplatin treatment markedly enhances the anticancer efficacy of cisplatin. In conclusion, ADAR1 promotes tumour progression and cisplatin resistance of iCCA. ADAR1 targeting could inform the development of innovative combination therapies for iCCA.

Background: Golgi phosphoprotein 3 (GOLPH3) has been frequently reported as an oncoprotein in a variety of tumors. However, its role in the cancer-associated intercellular signaling communication has not yet been explored. This study aimed at exploring whether GOLPH3 regulates angiogenesis and sorafenib resistance via exosomal mechanisms in hepatocellular carcinoma (HCC). Methods: In vivo assays were performed to elucidate the function of GOLPH3 in HCC. Exosomes of HCC cells were isolated by differential centrifugation, and then measured and quantified using nanoparticle tracking analysis (NTA), BCA assay, western blot (WB), and transmission electron microscopy (TEM). Differentially expressed miRNAs in exosome were analyzed and verified through small RNA sequencing (sRNA-seq) and reverse-transcription polymerase chain reaction (RT-PCR). In addition, a series of in vitro assays were performed to determine the function of exosomes and miR-494-3p in HCC. The candidate target gene of miR-494-3p was identified by bioinformatics prediction and dual-luciferase reporter assay. Results: Downregulation of GOLPH3 expression could suppress angiogenesis and enhance sorafenib sensitivity in HCC. Exosomes derived from GOLPH3 overexpression HCC cells promoted the angiogenesis ability of HUVECs and induced sorafenib resistance in HCC cells. A total of 13 differentially expressed miRNAs between negative control and GOLPH3 knockdown group were found in exosomes. However, GOLPH3 was only associated with miR-494-3p expression level in exosomes derived from HCC cells without affecting total cellular miR-494-3p content. Results confirmed that exosomal miR-494-3p promotes angiogenesis of HUVECs and sorafenib resistance in HCC cells through directly targeting PTEN. Conclusions: HCC cells with high expression levels of GOLPH3 could promote angiogenesis and sorafenib resistance by enhancing exosomal miR-494-3p secretion to recipient HUVECs and HCC cells, respectively.

Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1a^CreER;Prdm3^flox/flox mice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, Kras^G12D-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.