Background Metabolic rewiring of cancer cells reshapes the tumor microenvironment, thereby restricting the response to immunotherapy. Circular RNAs (circRNAs) can influence various cellular processes and have been implicated in hepatocellular carcinoma (HCC). Here, we investigated the role of a novel circRNA circRHBDD1 in HCC metabolic transformation and immunotherapy resistance. Methods CircRNA sequencing was performed to determine the differentially expressed circRNA profile in HCC. RT-qPCR and in situ hybridization were used to verify the dysregulation of circRHBDD1 in two independent HCC cohorts. Univariate and multivariate survival analyses were employed to assess the prognostic significance of circRHBDD1. Loss- and gain-of-function approaches were adopted to evaluate the effects of circRHBDD1 on glycolysis and glutaminolysis. Patient-derived xenograft models were used for in vivo evaluation. RNA pull-down, mass spectrometry, RNA immunoprecipitation, fluorescence in situ hybridization, polysome profiling, and meRIP assays were utilized to explore the molecular mechanisms of circRHBDD1 in HCC. Results We found that circRHBDD1 was significantly upregulated in HCC and associated with unfavorable clinicopathological characteristics and poor survival outcomes. In vitro and in vivo experiments showed that circRHBDD1 facilitated HCC glycolysis and glutaminolysis. Mechanistic studies revealed that circRHBDD1 could recruit YTHDF1 to PIK3R1 mRNA and augment PIK3R1 translation in an m 6 A-dependent manner, leading to activation of the PI3K/AKT signaling. EIF4A3-mediated exon back-splicing contributed to the upregulation of circRHBDD1. Moreover, targeting of circRHBDD1 was able to improve anti-PD-1 therapy resulting in prolonged survival. Conclusion We identified that the circRHBDD1/YTHDF1/PIK3R1 axis was crucial to metabolic reprogramming of HCC. Suppression of circRHBDD1 could potentially sensitize HCC cells to anti-PD-1 therapy.

BACKGROUND:Long non-coding RNAs (lncRNAs) possess significant regulatory functions in multiple biological and pathological processes, especially in cancer. Dysregulated lncRNAs in hepatocellular carcinoma (HCC) and their therapeutic applications remain unclear.METHODS:Differentially expressed lncRNA profile in HCC was constructed using TCGA data. LINC00958 expression level was examined in HCC cell lines and tissues. Univariate and multivariate analyses were performed to demonstrate the prognostic value of LINC00958. Loss-of-function and gain-of-function experiments were used to assess the effects of LINC00958 on cell proliferation, motility, and lipogenesis. Patient-derived xenograft model was established for in vivo experiments. RNA immunoprecipitation, dual luciferase reporter, biotin-labeled miRNA pull-down, fluorescence in situ hybridization, and RNA sequencing assays were performed to elucidate the underlying molecular mechanisms. We developed a PLGA-based nanoplatform encapsulating LINC00958 siRNA and evaluated its superiority for systemic administration.RESULTS:We identified a lipogenesis-related lncRNA, LINC00958, whose expression was upregulated in HCC cell lines and tissues. High LINC00958 level independently predicted poor overall survival. Functional assays showed that LINC00958 aggravated HCC malignant phenotypes in vitro and in vivo. Mechanistically, LINC00958 sponged miR-3619-5p to upregulate hepatoma-derived growth factor (HDGF) expression, thereby facilitating HCC lipogenesis and progression. METTL3-mediated N6-methyladenosine modification led to LINC00958 upregulation through stabilizing its RNA transcript. A PLGA-based nanoplatform loaded with si-LINC00958 was developed for HCC systemic administration. This novel drug delivery system was controlled release, tumor targeting, safe, and presented satisfactory antitumor efficacy.CONCLUSIONS:Our results delineate the clinical significance of LINC00958 in HCC and the regulatory mechanisms involved in HCC lipogenesis and progression, providing a novel prognostic indicator and promising nanotherapeutic target.

Background: Pancreatic ductal adenocarcinoma is a common malignancy with high morbidity. MicroRNAs have been demonstrated to be critical posttranscriptional regulators in tumorigenesis. This study aimed to investigate the effect of microRNA-590 on the proliferation and apoptosis of pancreatic ductal adenocarcinoma. Material and Methods: The expression of microRNA-590 and high mobility group AT-hook 2 were examined in clinical pancreatic ductal adenocarcinoma tissues. Pancreatic ductal adenocarcinoma cell line Capan-2 was employed and transfected with microRNA-590 mimics or inhibitor. The correlation between microRNA-590 and high mobility group AT-hook 2 was verified by luciferase reporter assay. Cell viability and apoptosis were detected by MTT and flow cytometry assay. The protein level of high mobility group AT-hook 2, AKT, p-AKT, mTOR, and phosphorylated mTOR were analyzed by Western blotting. Results: MicroRNA-590 was found to be negatively correlated with the expression of high mobility group AT-hook 2 in pancreatic ductal adenocarcinoma tissues. Further studies identified high mobility group AT-hook 2 as a direct target of microRNA-590. Moreover, overexpression of microRNA-590 downregulated expression of high mobility group AT-hook 2, reduced cell viability, and promoted cell apoptosis, while knockdown of miR-590 led to an inverse result. MicroRNA-590 also suppressed the phosphorylation of AKT and mTOR without altering total AKT and mTOR levels. Conclusion: Our study indicated that microRNA-590 negatively regulates the expression of high mobility group AT-hook 2 in clinical specimens andin vitro. MicroRNA-590 can inhibit cell proliferation and induce cell apoptosis in pancreatic ductal adenocarcinoma cells. This regulatory effect of microRNA-590 may be associated with AKT signaling pathway. Therefore, microRNA-590 has the potential to be used as a biomarker for predicting the progression of pancreatic ductal adenocarcinoma.

Circular RNAs (circRNAs) have emerged as crucial regulators of human cancers. Glutaminolysis supplies cancer cells with adequate nitrogen and carbon to replenish the tricarboxylic acid cycle, contributing to the survival and progression of tumor cells. However, the association between circRNAs and glutaminolysis remains unclear. In this study, we showed that circHECTD1 expression was markedly upregulated in gastric cancer (GC) and was associated with lymph node metastasis and American Joint Committee on Cancer stage. The circHECTD1 expression level was found to be an independent prognostic factor for GC patients. circHECTD1 knockdown inhibited GC cell glutaminolysis, proliferation, migration, and invasion, whereas circHECTD1 overexpression promoted GC progression. Dual-luciferase and RNA immunoprecipitation assays demonstrated that miR-1256 was a direct downstream target of circHECTD1. circHECTD1 targeted miR-1256 and subsequently increased the expression level of USP5. The circHECTD1/miR-1256/USP5 axis exerted its tumor-promoting effects by activating the downstream β-catenin/c-Myc signaling pathway. In vivo mouse models further verified the oncogenic roles of circHECTD1 in GC. Our results revealed that circHECTD1 is a glutaminolysis-associated circRNA that promotes GC progression. The circHECTD1/miR-1256/USP5 axis could thus be used as a therapeutic target for GC.

Background: Mounting evidence has indicated that long noncoding RNAs (lncRNAs) are promising candidates for tumor diagnosis and prognosis.Nonetheless, the significance of lncRNAs in colorectal cancer (CRC) diagnosis remains to be clarified.Here, we performed a comprehensive meta-analysis to evaluate the utility of lncRNAs as diagnostic indicators for CRC.Materials and Methods: Pertinent studies were searched using PubMed, PMC, Web of Science, Cochrane, and EMBASE database up to September 2018.Study quality was assessed with the Quality Assessment for Studies of Diagnostic Accuracy-2.Subgroup analyses by sample size and publication year were conducted.Threshold effect and meta-regression were performed to find the origin of heterogeneity.Statistical analyses were conducted using Stata and Meta-Disc.Results: A total of 19 studies with 3,114 individuals were enrolled in the current analysis.The overall sensitivity and specificity of lncRNAs in the diagnosis of CRC were 0.83 [95% confidence interval (CI): 0.76-0.87]and 0.84 (95% CI: 0.77-0.89),respectively.The pooled positive likelihood ratio was 5.11 (95% CI: 3.57-7.31),and the pooled negative likelihood ratio was 0.21 (95% CI: 0.15-0.28).The overall area under the curve was 0.90 (95% CI: 0.87-0.92),with a diagnostic odds ratio of 24.57(95% CI: 14.67-41.17).Conclusions: The accuracy of lncRNAs for CRC diagnosis is high, and lncRNAs could be functioned as promising candidates for CRC diagnosis.

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to enhance oxidative stress-mediated cancer cell death. Methods: A ROS-generating agent based on polymer-modified zinc peroxide nanoparticles (ZnO2 NPs) was presented, which simultaneously delivered exogenous H2O2 and Zn2+ capable of amplifying endogenous ROS production for synergistic cancer therapy. Results: After internalization into tumor cells, ZnO2 NPs underwent decomposition in response to mild acidic pH, resulting in controlled release of H2O2 and Zn2+. Intriguingly, Zn2+ could increase the production of mitochondrial O2·- and H2O2 by inhibiting the electron transport chain, and thus exerted anticancer effect in a synergistic manner with the exogenously released H2O2 to promote cancer cell killing. Furthermore, ZnO2 NPs were doped with manganese via cation exchange, making them an activatable magnetic resonance imaging contrast agent. Conclusion: This study establishes a ZnO2-based theranostic nanoplatform which achieves enhanced oxidative damage to cancer cells by a two-pronged approach of combining endogenous and exogenous ROS.

Accumulating evidence has indicated that microRNA (miRNA) dysregulation contributes to hepatocellular carcinoma (HCC) progression. miR-337-3p is downregulated in gastric cancer and neuroblastoma; however, its biological function and underlying mechanism in HCC remain unclear. In this study, we showed that the expression level of miR 337 3p was significantly decreased in HCC, and was associated with several clinicopathological characteristics, including tumor multiplicity, histological differentiation, and Barcelona Clinic Liver Cancer stage. Low expression level of miR-337-3p was associated with poor survival outcomes in HCC patients. Upregulation of miR337-3p suppressed cell proliferation, migration, and invasion in HCC. Dual luciferase assay demonstrated that JAK2 was a direct downstream target of miR-337-3p. JAK2 reintroduction restored the inhibited proliferation, migration, and invasion of miR-337-3p overexpressed HCC cells. miR-337-3p functioned as a tumor suppressor to modulate the JAK2/STAT3 signaling pathway. The present findings indicate that miR-337-3p could be used as a prognostic predictor and therapeutic candidate for HCC.