Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2. Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.

Circular RNAs (circRNAs) are identified as vital regulators in a variety of cancers. However, the role of circRNA in lung squamous cell carcinoma (LUSC) remains largely unknown. Herein, we explore the expression profiles of circRNA and mRNA in 5 paired samples of LUSC. By analyzing the co-expression network of differentially expressed circRNAs and dysregulated mRNAs, we identify that a cell cycle-related circRNA, circTP63 , is upregulated in LUSC tissues and its upregulation is correlated with larger tumor size and higher TNM stage in LUSC patients. Elevated circTP63 promotes cell proliferation both in vitro and in vivo. Mechanistically, circTP63 shares miRNA response elements with FOXM1. circTP63 competitively binds to miR-873-3p and prevents miR-873-3p to decrease the level of FOXM1, which upregulates CENPA and CENPB, and finally facilitates cell cycle progression.

Long noncoding RNAs (lncRNAs) have been associated with hepatocellular carcinoma (HCC), but the underlying molecular mechanisms of their specific association with hepatocarcinogenesis have not been fully explored.Methods: miR503HG was identified by microarray and validated by real-time PCR. Survival analysis was evaluated using the Kaplan-Meier method and assessed using the log-rank test. In vitro and in vivo assays were preformed to explore the biological effects of miR503HG in HCC cells. The interaction of miR503HG with HNRNPA2B1 was identified by RNA pull-down and RNA immunoprecipitation. Expression of HNRNPA2B1 was examined by western blotting, immunofluorescence and immunohistochemical analyses, while HNRNPA2B1 ubiquitination was detected by immunoprecipitation.Results: We have identified 713 differentially expressed lncRNAs in 12 pairs of HCC tissues compared with corresponding noncancerous liver tissues. One of these lncRNAs, miR503HG, the host gene of miR503, is markedly decreased in HCC. Expression level of miR503HG is significantly associated with the time to recurrence and overall survival and is an independent risk factor for recurrence and survival. Enhanced expression of miR503HG could noticeably inhibit HCC invasion and metastasis in vitro and in vivo. Further investigation suggested that miR503HG could specifically interact with the heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1). miR503HG promoted HNRNPA2B1 degradation via the ubiquitin-proteasome pathway, which reduced the stability of p52 and p65 mRNA, and simultaneously suppressed the NF-κB signaling pathway in HCC cells. In addition, miR503HG can function synergistically with miR503 to inhibit HCC migration.Conclusion: Our findings support a role for miR503HG in tumor recurrence risk and survival prediction in HCC patients. We demonstrate a novel mechanism by which miR503HG inhibits the NF-κB signaling pathway and exerts its metastatic tumor suppression function through modulating the ubiquitination status of HNRNPA2B1.

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Background and Aims Peroxisome proliferator‐activated receptor‐gamma (PPARγ) coactivator‐1α (PGC1α) is a key regulator of mitochondrial biogenesis and respiration. PGC1α is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in the progression of hepatocellular carcinoma (HCC) remains unclear. Approach and Results In this study, we observed that PGC1α was down‐regulated in human HCC. A clinical study showed that low levels of PGC1α expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1α inhibited the migration and invasion of HCC cells with both in vitro experiments and in vivo mouse models. Mechanistically, PGC1α suppressed the Warburg effect through down‐regulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by the WNT/β‐catenin pathway, and inhibition of the WNT/β‐catenin pathway was induced by activation of PPARγ. Conclusions Low levels of PGC1α expression indicate a poor prognosis for HCC patients. PGC1α suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating the WNT/β‐catenin/PDK1 axis, which depends on PPARγ. PGC1α is a potential factor for predicting prognosis and a therapeutic target for HCC patients.

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