Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial–mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA–MUF (MSC-upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA–MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA–MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA–MUF bound Annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA-mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting. Cancer Res; 77(23); 6704–16. ©2017 AACR.

Methyltransferase N6‑adenosine (METTL5) is a methyltransferase that specifically catalyzes 18S rRNA N6 methylation at adenosine 1832 (m⁶A₁₈₃₂), which is located in a critical position in the decoding center, therefore suggesting its potential importance in the regulation of translation. However, the underlying mechanism of METTL5‑mediated translation regulation of specific genes and its biological functions are largely undefined. To the best of our knowledge, the present study demonstrated for the first time that METTL5 was an oncogene that promoted cell proliferation, migration, invasion and tumorigenesis in pancreatic cancer. In addition, the oncogenic function of METTL5 may involve an increase in c‑Myc translation, as evidenced by the fact that the oncogenic effect caused by METTL5 overexpression could be abolished by c‑Myc knockdown. Notably, m⁶A modifications at the 5' untranslated region (5'UTR) and coding DNA sequence region (near the 5'UTR) of c‑Myc mRNA played a critical role in the specific translation regulation by METTL5. In addition, it was further demonstrated that METTL5 and its cofactor tRNA methyltransferase activator subunit 11‑2 synergistically promote pancreatic cancer progression. These findings revealed important roles for METTL5 in the development of pancreatic cancer and present the METTL5/c‑Myc axis as a novel therapeutic strategy for treatment.

Pancreatic cancer (PC) is one of the most aggressive and devastating types of cancer owing to its poor prognosis and deadly characteristics. It is well established that aberrations in the expression of key regulatory genes, namely tumor suppressors and oncogenes, predispose patients to progression and metastasis of PC. Upregulation of Williams‑Beuren syndrome chromosomal region 22 (WBSCR22) expression, a ribosomal biogenesis factor, has been reported in multiple types of human cancer. However, the role of WBSCR22 and its underlying mechanism in PC have not been well investigated. In the present study, the tumor suppressive role of WBSCR22 was reported in PC for the first time; the results indicated that WBSCR22 overexpression (OE) significantly suppressed cellular proliferation, migration, invasion and tumorigenesis in vivo and in vitro. RNA‑sequencing analysis revealed that WBSCR22 negatively regulated the transcription of interferon‑stimulated gene 15 (ISG15) downstream, which is a ubiquitin‑like modifier protein involved in metabolic and proteasome degradation pathways, while the antitumor function of WBSCR22‑OE could be rescued by ISG15 OE. In addition, the oncogenic role of ISG15 was further confirmed in PC; its upregulation promoted the proliferation, migration, invasion and tumorigenesis of PC. Furthermore, WBSCR22 and its cofactor tRNA methyltransferase activator subunit 11‑2 (TRMT112) functioned synergistically in PC, and concurrent ectopic OE of WBSCR22 and TRMT112 further promoted the tumor suppressive potential of WBSCR22 in PC. Collectively, the findings indicated that WBSCR22 played an important role in PC development and that the WBSCR22/ISG15 axis may provide a novel therapeutic strategy for PC treatment.

Emerging evidence suggests that epitranscriptional modifications influence multiple cellular processes. N6-methyladenosine (m⁶A), as the most abundant reversible methylation of mRNA, has also been reported to play critical roles in modulating embryonic stem cell differentiation and somatic cell reprogramming by regulating gene expression. This review examined the characteristics of m⁶A, including the distribution profile and currently discovered “writer,” “eraser,” and “reader” proteins. Moreover, the hypothesis is proposed that m⁶A could influence cell fate determination, and the underlying mechanisms are due to the related mRNA degradation, causing weakening of previous cell characteristics and eventually leading them to develop into the reverse direction (pluripotency or differentiation state). Accordingly, m⁶A modifications presented its potential role in cell fate determination, which provides new insights into understanding the mechanisms of various diseases.

Cancer stem-like cells (CSCs) are critical for the initiation, progression, chemoresistance and postsurgical recurrence of liver cancer. They are thought to be novel targets for the treatment of liver cancer, however, efficient agents that target liver cancer stem cells (CSCs) have not been identified. MicroRNAs (miRNAs) are small non-coding RNAs that target the 3untranslated region (3UTR) of mRNAs. Their dysregulation has been implicated in several types of cancer including liver cancer, but it still remains unknown if they play a role in targeting liver CSCs. We compared the miRNA profiles between liver cancer samples and adjacent non-tumor tissues using The Cancer Genome Atlas (TCGA) datasets. Several miRNAs including miR-486-5p (miR-486) were found to be significantly downregulated in liver cancer tissues. These differentially expressed miRNAs were screened between CSC-enriched tumor spheres and adherent cells. miR-486 was significantly downregulated in tumor spheres and liver cancer samples. Ectopic expression of miR-486 significantly repressed the self-renewal and invasion of CSCs in vitro and tumorigenesis in vivo. Notably, we found that sirtuin 1 (Sirt1) served as a direct target of miR-486. The high expression of Sirt1 was involved in maintaining the self-renewal and tumorigenic potential of liver CSCs. The results of the present study indicated that the miR-486-Sirt1 axis was involved in suppressing CSC traits and tumor progression.