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Background and purpose: The response rate of gastric cancer patients to programmed death-1 (PD-1) inhibitor is relatively low. Establishing a useful efficacy prediction method to screen the superior gastric cancer patients receiving anti-PD-1 therapy could improve the prognosis of patients. This study aimed to explore the value of combined detection of lactate dehydrogenase (LDHA) and programmed death ligand-1 (PD-L1) expressions in predicting the efficacy and prognosis of gastric cancer patients treated with PD-1 inhibitor. Methods: The clinicopathological data of 50 advanced gastric cancer patients treated with PD-1 inhibitor in The First Affiliated Hospital of Wannan Medical College from January 2020 to March 2022 were retrospectively analyzed. The independent risk factors affecting the efficacy of PD-1 inhibitor were analyzed by multivariate logistic regression. The value of combined detection of LDHA and PD-L1 in predicting the efficacy of PD-1 inhibitors in gastric cancer was analyzed by receiver operating characteristic (ROC) curve analysis. Gastric cancer patient survival was analyzed by Kaplan-Meier method. Results: The objective response rate (ORR) of gastric cancer patients receiving PD-1 inhibitor therapy in LDHA low and high expression groups were 59% and 10%, respectively. The disease control rate (DCR) in LDHA low and high expression groups were 83% and 29%, respectively. The difference was statistically significant (P

Background and purpose: Gastric cancer is one of the most common malignant tumors of digestive system. Previous study demonstrated that circSMARCA5 was downregulated and could function as a tumor suppressor in gastric cancer. However, the molecular mechanism has not yet been documented. This study aimed to investigate the effects of circSMARCA5 on the proliferation and invasion of gastric cancer cells and their molecular mechanisms. Methods: Cell counting kit-8 (CCK-8) assays and transwell assays were performed to examine the cell proliferative and invasive abilities, respectively. The effect of circSMARCA5 on gastric cancer cell glycolysis was assessed by detecting the extracellular acidification rate, glucose uptake level and lactate production. Real-time fluorescent quantitative polymerase chain reaction (RTFQ-PCR) assay was performed to detect the expression levels of circSMARCA5, miR-4295 and PTEN. The levels of GLUT1 and LDHA were measured by Western blot assay. The transplanted xenograft model in nude mice was established, and the effects of circSMARCA5 on the tumor growth were observed. Immunohistochemistry assays were performed to examine the expression levels of GLUT1, LDHA and Ki-67 proliferation index in xenograft tumors. Dual luciferase reporter gene assays, Pearson's correlation analysis and RNA immunoprecipitation (RIP) assays were used to confirm the targeting relationship of circSMARCA5 and miR-4295 as well as miR-4295 and PTEN. Results: CircSMARCA5 overexpression inhibited the proliferation and invasion of gastric cancer cells. Compared to the control group, the glycolysis rate, glycolysis capacity, glucose uptake and lactate production in the circSMARCA5-overexpresing group were significantly decreased. In addition, nude mouse transplanted xenograft assays showed that the volume and the weight of the tumors in the circSMARCA5-overexpressing group were lower compared with the control group. Further studies indicated that circSMARCA5 acted as a molecular sponge to inhibit the expression of miR-4295. Besides, miR-4295 could inhibit the expression of PTEN by binding with the 3'-UTR of PTEN mRNA. Rescue experiments by upregulating miR-4295 or downregulating PTEN expression in the circSMARCA5-overexpressing gastric cancer cells were performed, and the results showed that upregulation of miR-4295 or PTEN knockdown could abolish the inhibitory effects of circSMARCA5 overexpression on cell proliferation, invasion and glycolysis. Conclusion: CircSMARCA5 suppresses the proliferation and invasion of gastric cancer cells by targeting miR-4295, increasing the expression level of PTEN and subsequently regulating glycolysis.

Circular RNAs (circRNAs), a novel class of non‐coding RNAs, have emerged as indispensable modulators in human malignancies. Aberrant cellular senescence is a phenotype observed in various cancers. The association of circRNAs with cellular senescence in tumors is yet to determined. Here, we investigated the role of circLARP4 in cellular senescence and cell proliferation in hepatocellular carcinoma (HCC). Downregulated circLARP4 level was observed in HCC tissues and cell lines. Low expression level of circLARP4 independently predicted poor survival outcome. Gain‐of‐function and loss‐of‐function assays demonstrated that circLARP4 suppressed HCC cell proliferation, mediated cell cycle arrest and induced senescence in vitro. Levels of p53 and p21, 2 key regulatory molecules in cellular senescence, were increased in circLARP4‐overexpressed HCC cells and decreased in circLARP4‐silenced HCC cells. In vivo experiments further confirmed the tumor‐suppressing activity of circLARP4. Further mechanistic studies showed that circLARP4 dampened HCC progression by sponging miR‐761, thereby promoting the expression level of RUNX3 and activating the downstream p53/p21 signaling. Our study revealed the role of circLARP4/miR‐761/RUNX3/p53/p21 signaling in HCC progression, providing a potential survival predictor and therapeutic candidate for HCC. circLARP4 is downregulated in hepatocellular carcinoma. circLARP4 suppresses hepatocellular carcinoma cell proliferation, mediates cell cycle arrest and induces senescence. circLARP4 dampens hepatocellular carcinoma progression by sponging miR‐761, thereby promoting the expression of RUNX3 and activating the downstream p53/p21 signaling. [ABSTRACT FROM AUTHOR]

Circular RNAs are a class of highly conserved RNAs with stable covalently closed circular structures. Metabolic reprogramming of cancer cells reshapes the tumor microenvironment and can suppress antitumor immunity. Here, we discovered a novel circular RNA, termed circRHBDD1, which augments aerobic glycolysis and restricts anti-PD-1 therapy in hepatocellular carcinoma (HCC). Mechanistic studies revealed that circRHBDD1 recruits the m 6 A reader YTHDF1 to PIK3R1 mRNA and accelerates the translation of PIK3R1 in an m 6 A-dependent manner. EIF4A3-mediated exon back-splicing contributes to the upregulation of circRHBDD1. Moreover, circRHBDD1 is highly expressed in anti-PD-1 responder HCC patients, and targeting circRHBDD1 improves anti-PD-1 therapy in an immune-competent mouse model. Overall, these findings illustrate the metabolic importance of the circRHBDD1/YTHDF1/PIK3R1 axis in HCC and show that suppression of circRHBDD1 may bolster the efficacy of anti-PD-1 therapy for HCC treatment., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Background and Aims: The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor-associated macrophages (TAMs) are deemed a key factor for the tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro-metastatic effect of TAMs on HCC remains undefined., Approach and Results: The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2-polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo. Furthermore, we found that M2-derived exosomes induced TAM-mediated pro-migratory activity. With the use of mass spectrometry, we identified that integrin, α M β 2 (CD11b/CD18), was notably specific and efficient in M2 macrophage-derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos-mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase-9 signaling pathway in recipient HCC cells to support tumor migration., Conclusions: Collectively, the exosome-mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis., (© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

MicroRNAs (miRNAs) have been reported to play an essential role in tumor development and progression. However, the function of miR-621 in hepatocellular carcinoma (HCC) remains largely unexplored. In this study, we found that miR-621 was downregulated in the HCC specimens and cell lines, and lower expression of miR-621 indicated poor survival. Overexpression of miR-621 was shown to induce G0/G1 cell cycle arrest and inhibit cell proliferation in vitro and in vivo . Luciferase assays revealed that cell cycle-associated protein 1 (CAPRIN1) is a novel functional downstream target of miR-621. miR-621 could regulate c-MYC and cyclin D2 expression by directly targeting CAPRIN1. Further study revealed that CAPRIN1 was upregulated in the HCC specimens and cell lines. Restoration of CAPRIN1 neutralized the miR-621-induced cell cycle arrest and cell proliferation inhibition. Taken together, our findings suggest that miR-621 acts as a tumor suppressor gene in HCC progression by downregulating CAPRIN1 expression and could be a novel potential diagnostic and prognostic biomarker for HCC., Competing Interests: None.