Epidemiological, preclinical and cellular studies in the last 5 years have shown that metformin exerts anti‐tumoral properties, but its mode of action in cancer remains unclear. Here, we investigated the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and tumor‐associated T cell immune responses. Oral metformin administration led to a significant reduction of tumor growth, which was accompanied by decreased interleukin‐22 (IL‐22). Meanwhile, IL‐22‐induced STAT3 phosphorylation and upregulation of downstream genes Bcl‐2 and cyclin D1 were inhibited by metformin. At the cellular level, metformin attenuated Th1‐ and Th17‐derived IL‐22 production. Furthermore, metformin inhibited de novo generation of Th1 and Th17 cells from naive CD4⁺ cells. These observations were further supported by the fact that metformin treatment inhibited CD3/CD28‐induced IFN‐γ and IL‐17A expression along with the transcription factors that drive their expression (T‐bet [Th1] and ROR‐γt [Th17], respectively). The effects of metformin on T cell differentiation were mediated by downregulated STAT3 and STAT4 phosphorylation via the AMP‐activated kinase‐mammalian target of rapamycin complex 1 pathway. Notably, metformin led to a reduction in glucose transporter Glut1 expression, resulting in less glucose uptake, which is critical to regulate CD4⁺ T cell fate. Taken together, these findings provide evidence for the growth‐inhibitory and immune‐modulatory effects of metformin in HCC and thus, broaden our understanding about the action of metformin in liver cancer treatment.

Background: Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity and may play an important role in carcinogenesis. We investigated the role of genetic polymorphisms at XRCC4 codon 247 (rs3734091, XRCC4P) and XRCC5 codon 180 (rs80309960, XRCC5P) in liver cancer (hepatocellular carcinoma) caused by aflatoxin B1 (AFB1). Methods: A hospital-based case-control study, including 1499 liver cancer cases and 2045 controls without any liver disease, was conducted in a high aflatoxin exposure area in the Guangxi region of China to assess the relationship between these two polymorphisms and aflatoxin-related liver cancer risk and prognosis. Genotypes, mRNA levels, and the hot-spot mutation of TP53 gene (TP53M) related to AFB1 exposure was tested using TaqMan-PCR technique. XRCC4 protein level was analyzed by immunohistochemistry. Results: For XRCC4P and XRCC5P, only XRCC4P modified liver cancer risk. Compared with the homozygote of XRCC4 codon 247 Ala alleles (XRCC4-AA), the genotypes of XRCC4 codon 247 Ser alleles (namely XRCC4-AS or -SS) increased liver cancer risk (odds ratio [OR] = 1.35 and 2.02, respectively). Significant interactive effects between risk genotypes (OR > 1) and aflatoxin exposure status were also observed in the joint effects analysis. Moreover, this polymorphism was associated not only with lower XRCC4 expression levels but also with higher AFB1-DNA adduct levels and increasing TP53M and portal vein tumor risk. Additionally, XRCC4P modified the recurrence-free survival and overall survival of cases, especially under conditions of high aflatoxin exposure. Conclusion: XRCC4P may be a genetic modifier for the risk and outcome of hepatocellular carcinoma induced by AFB1 exposure.

MicroRNA-24 (miR-24) may be involved in neoplastic process; however, the role of this microRNA in the hepatocellular carcinoma (HCC) related to aflatoxin B1 (AFB1) has not been well elaborated. Here, we tested miR-24 expression in 207 pathology-diagnosed HCC cases from high AFB1 exposure areas and HCC cells. We found that miR-24 was upregulated in HCC tumor tissues relative to adjacent noncancerous tissue samples, and that the high expression of miR-24 was significantly correlated with larger tumor size, higher microvessel density, and tumor dedifferentiation. Additionally, this microRNA overexpression modified the recurrence-free survival (relative hazard ratio [HR], 4.75; 95% confidence interval [CI], 2.66–8.47) and overall survival (HR=3.58, 95% CI = 2.34–5.46) of HCC patients. Furthermore, we observed some evidence of joint effects between miR-24 and AFB1 exposure on HCC prognosis. Functionally, miR-24 overexpression progressed tumor cells proliferation, inhibited cell apoptosis, and developed the formation of AFB1-DNA adducts. These results indicate for the first time that miR-24 may modify AFB1-related HCC prognosis and tumorigenesis.

Our recent investigations showed that polycomb chromobox 4 (Cbx4) promotes angiogenesis and metastasis of hepatocellular carcinoma (HCC) through its sumoylating action on hypoxia-inducible factor-1α protein. Here, we attempt to identify the prognostic significances of Cbx4 by a retrospective analyses in 727 cases of HCC patients with and without postoperative transarterial chemoembolization (TACE) or transarterial embolization (TAE). Binary logistic regression tests indicated that Cbx4 is correlated with histological grading, tumor-node-metastasis stage, microvessel density, distant metastasis and hematogenous metastasis of HCC. By univariate and multivariate analyses, we show that Cbx4 is an independent prognostic factor of HCC, and both TAE and TACE treatments have no effects on the overall survival in HCC patients with low Cbx4 expression. More intriguingly, TACE prolongs, while TAE shortens, the overall survival of HCC patients with high Cbx4 expression, indicating that Cbx4 is a good biomarker on decision-making to perform postoperative TACE in HCC patients. Moreover, Cbx4 overexpression enhances while Cbx4 silencing antagonizes doxorubicin-induced cell death of HCC cell lines. In conclusion, Cbx4 is an independent prognostic factor for HCC patients, and the patients with high Cbx4 expression should receive postoperative TACE treatment to improve their survival.

MicroRNA-429 (miR-429) may modify the development and progression of cancers; however, the role of this microRNA in the hepatocellular carcinoma (HCC) has not been well elaborated. Here, we tested miR-429 expression in 138 pathology-diagnosed HCC cases and SMMC-7721 cells. We found that miR-429 was upregulated in HCC tumor tissues and that the high expression of miR-429 was significantly correlated with larger tumor size (odd ratio (OR), 2.70; 95% confidence interval (CI), 1.28–5.56) and higher aflatoxin B1-DNA adducts (OR = 3.13, 95% CI = 1.47–6.67). Furthermore, this microRNA overexpression modified the recurrence-free survival and overall survival of HCC patients. Functionally, miR-429 overexpression progressed tumor cells proliferation and inhibited cell apoptosis. These results indicate for the first time that miR-429 may modify HCC prognosis and tumorigenesis and may be a potential tumor therapeutic target.

Background: The recent surge in incidence and geographic spread of OROV infections poses an escalating threat to global public health. However, studies exploring the clinical signs of OROV infection remains exceedingly limited. Methods: We searched for OROV studies published until June 17, 2024, in several electronic databases including MEDLINE, EMBASE, SCOPUS, and the Cochrane Library. Results: In total, 15 studies involving 806 patients with OROV infection were eligible for inclusion. General symptoms with fever and headache were the most common. Gastrointestinal disturbances like nausea/vomiting, anorexia, and odynophagia were also prevalent, along with ocular symptoms, mainly retro-orbital pain, photophobia, and redness. Respiratory symptoms, such as cough, sore throat and nasal congestion, are present, and skin-related issues like rash, pruritus, and pallor were also identified. Conclusion: Overall, this study provides a foundational understanding of OROV’s clinical manifestations to guide diagnosis, management, and public health interventions against this neglected tropical disease.