Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the second most lethal human cancer. A portion of patients with advanced HCC can significantly benefit from treatments with sorafenib, adriamycin, 5-fluorouracil and platinum drugs. However, most HCC patients eventually develop drug resistance, resulting in a poor prognosis. The mechanisms involved in HCC drug resistance are complex and inconclusive. Human transcripts without protein-coding potential are known as noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and circular RNA (circRNA). Accumulated evidences demonstrate that several deregulated miRNAs and lncRNAs are important regulators in the development of HCC drug resistance which elucidates their potential clinical implications. In this review, we summarized the detailed mechanisms by which miRNAs and lncRNAs affect HCC drug resistance. Multiple tumor-specific miRNAs and lncRNAs may serve as novel therapeutic targets and prognostic biomarkers for HCC.

Circular RNAs (circRNA) are a group of noncoding, covalently uninterrupted loop transcripts, most of which remain to be functionally characterized. Here, we identified circPDIA4 as an oncogenic circRNA in gastric cancer. Clinically, circPDIA4 was significantly upregulated in malignant tissues and was associated with poor survival of patients with gastric cancer. The biogenesis of circPDIA4 was mediated by the RNA-binding protein Quaking, which bound introns 2 and 4 of PDIA4 pre-mRNA to promote backsplicing of exons 3 and 4. Elevated expression of circPDIA4 promoted distant metastasis in various mouse xenograft models in vivo and accelerated cancer cell invasion in vitro. CircPDIA4 functioned through distinct oncogenic mechanisms in the cytoplasm and the nucleus. Cytoplasmic circPDIA4 bound to ERK1/2 and sustained hyperactivation of the MAPK pathway by preventing DUSP6-mediated ERK1/2 dephosphorylation. Notably, circPDIA4 depletion enhanced the sensitivity of gastric cancer cells to ERK inhibitors. In the nucleus, circPDIA4 interacted with DHX9 as a decoy and repressed its inhibitory functions on circRNA biogenesis to boost expression of multiple oncogenic circRNAs, which promoted gastric cancer progression. These findings reveal a dual tumor-promoting mechanism for circPDIA4 by regulating oncogenic circRNA biogenesis and increasing MAPK activity. CircPDIA4 should be investigated further as a potential prognostic biomarker and therapeutic target in gastric cancer. Significance: Quaking-regulated circPDIA4 mediates different mechanisms in the nucleus and cytoplasm that coordinate to promote progression and drug resistance in gastric cancer.

Hepatocellular carcinoma (HCC) is one of the most lethal neoplasms and has a 5-year survival rate of only 18% in patients with metastatic diseases. Epigenetic modifiers and alterations, including histone modifications, long noncoding RNAs (lncRNA), RNA alternative splicing, and N6-methyladenosine (m6A) modification, are key regulators of HCC development, highlighting the importance of understanding the cross-talk between these biological processes. In the current study, we identified LINC01089 as a super enhancer (SE)–driven lncRNA that promotes epithelial–mesenchymal transition (EMT), migration, invasion, and metastasis of HCC cells in vivo and in vitro. The transcription factor E2F1 bound to a LINC01089 SE, promoting LINC01089 transcription and overexpression. LINC01089 interacted with heterogeneous nuclear ribonucleoprotein M (hnRNPM) and led to hnRNPM-mediated skipping of DIAPH3 exon 3. Knockdown of LINC01089 increased the inclusion of DIAPH3 exon 3, which contains an important m6A-modification site that is recognized by IGF2BP3 to increase DIAPH3 mRNA stability. Thus, LINC01089 loss increased DIAPH3 protein levels, which suppressed the ERK/Elk1/Snail axis and inhibited EMT of HCC cells. In conclusion, this study revealed cross-talk between different epigenetics modifiers and alterations that drives HCC progression and identified LINC01089 as a potential prognostic marker and therapeutic target for HCC. Significance: LINC01089 is a super enhancer–driven long noncoding RNA that induces ERK signaling and epithelial–mesenchymal transition by regulating DIAPH3 alternative splicing that blocks N6-methyladenosine–mediated mRNA stabilization, establishing an epigenetic network that promotes hepatocellular carcinoma metastasis.