The treatment for hepatocellular carcinoma (HCC) is promising in recent years, but still facing critical challenges. The first targeted therapy, sorafenib, prolonged the overall survival by months. However, resistance often occurs, largely limits its efficacy. Sorafenib was found to target the electron transport chain complexes, which results in the generation of reactive oxygen species (ROS). To maintain sorafenib resistance and further facilitate tumor progression, cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death. In the present study, we investigated the roles of ROS in sorafenib resistance, and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells. Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib. However, cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells. Further investigation attributed this finding to decreased mitochondrial biogenesis, likely caused by the accelerated degradation of peroxisome proliferator-activated receptor γ coactivator 1β (PGC1β). Mechanistic dissection showed that upregulated UBQLN1 induced PGC1β degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment. Furthermore, clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival. In conclusion, we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance, which may offer new therapeutic targets and strategies for HCC patients.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies globally. Despite aggressive and multimodal treatment regimens, the overall survival of HCC patients remains poor. Main: Circular RNAs (circRNAs) are noncoding RNAs (ncRNAs) with covalently closed structures and tissue- or organ-specific expression patterns in eukaryotes. They are highly stable and have important biological functions, including acting as microRNA sponges, protein scaffolds, transcription regulators, translation templates and interacting with RNA-binding protein. Recent advances have indicated that circRNAs present abnormal expression in HCC tissues and that their dysregulation contributes to HCC initiation and progression. Furthermore, researchers have revealed that some circRNAs might serve as diagnostic biomarkers or drug targets in clinical settings. In this review, we systematically evaluate the characteristics, biogenesis, mechanisms and functions of circRNAs in HCC and further discuss the current shortcomings and potential directions of prospective studies on liver cancer-related circRNAs. Conclusion: CircRNAs are a novel class of ncRNAs that play a significant role in HCC initiation and progression, but their internal mechanisms and clinical applications need further investigation.

Background: Pancreatic adenocarcinoma is a highly lethal malignancy. Neoadjuvant chemo(radio)therapy [NAC(R)T] is recommended to use for borderline resectable pancreatic cancer (BRPC) and high-risk resectable pancreatic cancer (RPC), but no high-level evidence exists. Methods: We searched PubMed, EMBASE, Web of Science, and Cochrane library to identify trials comparing survival data of NAC(R)T with SF for RPC or BRPC. Overall survival (OS) was synthesized in analysis of all the patients (intention-to-treat [ITT] analysis) and resected patients respectively. Results: The meta-analysis included 17 trials with 2286 participants. For BRPC, NAC(R)T improved OS both in ITT analysis (HR, 0.49; 95% CI, 0.37–0.65; P < 0.001) and in analysis of resected patients (HR, 0.66; 95% CI, 0.51–0.85; P = 0.001) in comparison to SF, accompanied with comparable overall resection rate [odds ratio (OR), 0.69; 95% Cl, 0.41–1.16; P = 0.159]. Disease-free survival, R0 rate, and recurrence were also in favor of NAC(R)T. For RPC, OS in analysis of resected patients was higher with NAC(R)T (HR, 0.75; 95% CI, 0.63–0.89; P = 0.001), but OS in ITT analysis was similar (HR, 1.02; 95% CI, 0.85–1.22; P = 0.818). The overall resection rate (OR, 0.50; 95% Cl, 0.25–0.99; P = 0.048) was lower, but R0 rate was higher with NAC(R)T. No differences in disease-free survival and recurrence between NAC(R)T and SF. Survival benefits of NAC(R)T basically persisted across sensitivity and subgroup analyses. Conclusions: This meta-analysis demonstrates that NAC(R)T can provide survival benefits in BRPC patients and a subgroup of RPC patients compared with SF. Future research should focus on investigating the potential biomarkers to screen the subgroup of RPC patients who can benefit from neoadjuvant therapy. Trial registration: CRD42018103086.

Circular RNAs (circRNAs) have emerged as important regulators of various cellular processes and have been implicated in cancer. Previously, we reported the discovery of several dysregulated circRNAs including circPABPC1 (polyadenylate-binding protein 1) in human hepatocellular carcinoma (HCC), although their roles in HCC development remained unclear. Here, we show that circPABPC1 is preferentially lost in tumor cells from clinical samples and inhibits both intrahepatic and distant metastases in a mouse xenograft model. This tumor-suppressive function of circPABPC1 can be attributed to its inhibition of cell adhesion and migration through down-regulating a key member of the integrin family, ITGB1 (β₁ integrin). Mass spectrometry and biochemical evidence demonstrate that circPABPC1 directly links ITGB1 to the 26S proteasome for degradation in a ubiquitination-independent manner. Our data have revealed an uncanonical route for integrin turnover and a previously unidentified mode of action for circRNAs in HCC that can be harnessed for anticancer treatment.

Gastrointestinal cancer (GIC) is the most prevalent and highly metastatic malignant tumor and has a significant impact on mortality rates. Nevertheless, the swift advancement of contemporary technology has not seamlessly aligned with the evolution of detection methodologies, resulting in a deficit of innovative and efficient clinical assays for GIC. Given that exosomes are preferentially released by a myriad of cellular entities, predominantly originating from neoplastic cells, this confers exosomes with a composition enriched in cancer-specific constituents. Furthermore, exosomes exhibit ubiquitous presence across diverse biological fluids, endowing them with the inherent advantages of non-invasiveness, real-time monitoring, and tumor specificity. The unparalleled advantages inherent in exosomes render them as an ideal liquid biopsy biomarker for early diagnosis, prognosticating the potential development of GIC metastasis.In this review, we summarized the latest research progress and possible potential targets on cancer-derived exosomes (CDEs) in GIC with an emphasis on the mechanisms of exosome promoting cancer metastasis, highlighting the potential roles of CDEs as the biomarker and treatment in metastatic GIC.

A major obstacle for treatment of HCC is the inadequate efficacy and limitation of the available therapeutic options. Despite the recent advances in developing novel treatment options, HCC still remains one of the major causes of cancer morbidity and mortality around the world. Achieving effective treatment and eradication of HCC is a challenging task, however recent studies have shown that targeting Natural Killer cells, as major regulators of immune system, can help with the complete treatment of HCC, restoration of normal liver function and subsequently higher survival rate of HCC patients. Studies have shown that decrease in the frequency of NK cells, their dysfunction due to several factors such as dysregulation of receptors and their ligands, and imbalance of different types of inhibitory and stimulating microRNA expression is associated with higher rate of HCC progression and development, and poor survival outcome. Here in our review, we mainly focused on the importance of NK cells in HCC development and treatment.