Hepatitis B virus (HBV) infection is a major driver of hepatocarcinogenesis. Ferroptosis is a type of iron-mediated cell death that can suppress liver transformation. Previous studies have linked HBV to ferroptosis in liver fibrosis and acute liver failure. However, whether ferroptosis is involved in HBV-mediated liver cancer is poorly understood. Here, we identified heat shock protein family A member 8 (HSPA8) as a crucial host factor that modulates HBV replication and ferroptosis in liver cancer. Hepatitis B X protein (HBx) upregulated HSPA8 by coactivating the transcription factor heat shock factor 1 (HSF1) in cells. HSPA8 enhanced HBV replication by recruiting hepatitis B core protein (HBc) to the HBV covalently closed circular DNA (cccDNA) minichromosome, forming a positive feedback loop. Moreover, HSPA8 suppressed ferroptosis in liver cancer cells by upregulating the expression of SLC7A11/GPX4 and decreasing erastin-mediated reactive oxygen species and Fe2+ accumulation in cells in vitro and in vivo. Inhibition of HSPA8 reduced the growth of HBV-positive liver tumors and increased sensitivity to erastin. In conclusion, HBx-elevated HSPA8 regulates both HBV replication and ferroptosis in liver cancer. Targeting HSPA8 could be a promising strategy for controlling HBV and hepatocarcinogenesis. Significance: HBV-induced upregulation of HSPA8 promotes hepatocarcinogenesis by suppressing ferroptosis and stimulating HBV replication, identifying HSPA8 as a potential therapeutic target in liver cancer.

A number of studies have shown that aspirin, as commonly prescribed drug, prevents the development of hepatocellular carcinoma (HCC). Ferroptosis as a dynamic tumor suppressor plays a vital role in hepatocarcinogenesis. In this study we investigated whether aspirin affected ferroptosis in liver cancer cells. RNA-seq analysis revealed that aspirin up-regulated 4 ferroptosis-related drivers and down-regulated 5 ferroptosis-related suppressors in aspirin-treated HepG2 cells. Treatment with aspirin (4 mM) induced remarkable ferroptosis in HepG2 and Huh7 cells, which was enhanced by the ferroptosis inducer erastin (10 μM). We demonstrated that NF-κB p65 restricted ferroptosis in HepG2 and Huh7 cells through directly binding to the core region of SLC7A11 promoter and activating the transcription of ferroptosis inhibitor SLC7A11, whereas aspirin induced ferroptosis through inhibiting NF-κB p65-activated SLC7A11 transcription. Overexpression of p65 rescued HepG2 and Huh7 cells from aspirin-induced ferroptosis. HCC patients with high expression levels of SLC7A11 and p65 presented lower survival rate. Functionally, NF-κB p65 blocked the aspirin-induced ferroptosis in vitro and in vivo, which was attenuated by erastin. We conclude that aspirin triggers ferroptosis by restricting NF-κB-activated SLC7A11 transcription to suppress the growth of HCC. These results provide a new insight into the mechanism by which aspirin regulates ferroptosis in hepatocarcinogenesis. A combination of aspirin and ferroptosis inducer may provide a potential strategy for the treatment of HCC in clinic.

Background: Colorectal cancer (CRC) is a major cancer burden, and prognosis is determined by many demographic and clinicopathologic factors. The present study aimed to construct a prognostic nomogram for colorectal cancer patients with distant metastasis. Methods: Colorectal cancer patients with distant metastasis diagnosed between 2010 and 2016 were selected from the Surveillance, Epidemiology, and End Results database. Cox proportional hazards regression was used to identify independent prognostic factors. A nomogram was constructed to predict survival, and validation was performed. Results: A total of 7099 stage IV colorectal cancer patients were enrolled in the construction cohort. The median overall survival was 20.0 (95% CI 19.3–20.7) months. Age at diagnosis, marital status, race, primary tumour site, tumour grade, CEA level, T stage, N stage, presence of bone, brain, liver and lung metastasis, surgery for primary site and performance of chemotherapy were independent prognostic factors. The nomogram was constructed and the calibration curve showed satisfactory agreement. The C-index was 0.742 (95% CI 0.726–0.758). In the validation cohort (7098 patients), the nomogram showed satisfactory discrimination and calibration with a C-index of 0.746 (95% CI 0.730–0.762). Conclusion: A series of factors associated with the survival of CRC patients with distant metastasis were found. Based on the identified factors, a nomogram was generated to predict the survival of stage IV colorectal cancer patients. The predictive model showed satisfactory discrimination and calibration, which can provide a reference for survival estimation and individualized treatment decisions.

The Nectin cell adhesion molecule (Nectin) family members are Ca²⁺‑independent immunoglobulin‑like cellular adhesion molecules (including Nectins 1‑4), involved in cell adhesion via homophilic/heterophilic interplay. In addition, the Nectin family plays a significant role in enhancing cellular viability and movement ability. In contrast to enrichment of Nectins 1‑3 in normal tissues, Nectin‑4 is particularly overexpressed in a number of tumor types, including breast, lung, urothelial, colorectal, pancreatic and ovarian cancer. Moreover, the upregulation of Nectin‑4 is an independent biomarker for overall survival in numerous cancer types. A large number of studies have revealed that high expression of Nectin‑4 is closely related to tumor occurrence and development in various cancer types, but the manner in which Nectin‑4 protein contributes to the onset and development of these malignancies is yet unknown. The present review summarizes the molecular mechanisms and functions of Nectin‑4 protein in the biological processes and current advances with regard to its expression and regulation in various cancer types.

The purpose of the present study was to characterize the prevalence, associated factors, and to construct a nomogram for predicting bone metastasis (BM) with different histological types of lung cancer. This study was a descriptive study that basing on the invasive lung cancer patients diagnosed between 2010 and 2014 in Surveillance, Epidemiology, and End Results program. A total of 125,652 adult patients were retrieved. Logistic regression analysis was conducted to investigate homogeneous and heterogeneous factors for BM occurrence. Nomogram was constructed to predict the risk for developing BM and the performance was evaluated by the receiver operating characteristics curve (ROC) and the calibration curve. The overall survival of the patients with BM was analyzed using the Kaplan–Meier method and the survival differences were tested by the log-rank test. A total of 25,645 (20.9%) were reported to have BM, and the prevalence in adenocarcinoma, squamous cell carcinoma, small cell lung cancer (SCLC), large cell lung cancer (LCLC), and non-small cell lung cancer/not otherwise specified lung cancer (NSCLC/NOS) were 24.4, 12.5, 24.7, 19.5 and 19.4%, respectively, with significant difference (P < 0.001). Male gender, more metastatic sites and lymphatic metastasis were positively associated with BM in all lung cancer subtypes. Larger tumor size was positively associated with BM in all the lung cancer subtypes except for NSCLC/NOS. Poorly differentiated histology was positively associated with adenocarcinoma, squamous cell carcinoma and NSCLC/NOS. The calibration curve and ROC curve exhibited good performance for predicting BM. The median survival of the bone metastatic lung cancer patients was 4.00 (95%CI: 3.89–4.11) months. With the increased number of the other metastatic sites (brain, lung and liver metastasis), the survival significantly decreased (p < 0.001). Different lung cancer histological subtypes exhibited distinct prevalence and homogeneity and heterogeneity associated factors for BM. The nomogram has good calibration and discrimination for predicting BM of lung cancer.