Background: Benzo[a]pyrene (B[a]P), a carcinogen pollutant produced by combustion processes, is present in the western diet with grilled meats. Chronic exposure of B[a]P in hepatocellular carcinoma (HCC) cells promotes metastasis rather than primary proliferation, implying an unknown mechanism of B[a]P‐induced malignancy. Given that exosomes carry bioactive molecules to distant sites, we investigated whether and how exosomes mediate cancer‐stroma communications for a toxicologically associated microenvironment. Method: Exosomes were isolated from B[a]P stimulated BEL7404 HCC cells (7404‐100Bap Exo) at an environmental relevant dose (100 nmol/L). Lung pre‐education animal model was prepared via injection of exosomes and cytokines. The inflammatory genes of educated lungs were evaluated using quantitative reverse transcription PCR array. HCC LM3 cells transfected with firefly luciferase were next injected to monitor tumor burdens and organotropic metastasis. Profile of B[a]P‐exposed exosomes were determined by ceRNA microarray. Interactions between circular RNA (circRNA) and microRNAs (miRNAs) were detected using RNA pull‐down in target lung fibroblasts. Fluorescence in situ hybridization and RNA immunoprecipitation assay was used to evaluate the “on‐off” interaction of circRNA‐miRNA pairs. We further developed an adeno‐associated virus inhalation model to examine mRNA expression specific in lung, thereby exploring the mRNA targets of B[a]P induced circRNA‐miRNA cascade. Results: Lung fibroblasts exert activation phenotypes, including focal adhesion and motility were altered by 7404‐100Bap Exo. In the exosome‐educated in vivo model, fibrosis factors and pro‐inflammatory molecules of are up‐regulated when injected with exosomes. Compared to non‐exposed 7404 cells, circ_0011496 was up‐regulated following B[a]P treatment and was mainly packaged into 7404‐100Bap Exo. Exosomal circ_0011496 were delivered and competitively bound to miR‐486‐5p in recipient fibroblasts. The down‐regulation of miR‐486‐5p converted fibroblast to cancer‐associated fibroblast via regulating the downstream of Twinfilin‐1 (TWF1) and matrix metalloproteinase‐9 (MMP9) cascade. Additionally, increased TWF1, specifically in exosomal circ_0011496 educated lungs, could promote cancer‐stroma crosstalk via activating vascular endothelial growth factor (VEGF). These modulated fibroblasts promoted endothelial cells angiogenesis and recruited primary HCC cells invasion, as a consequence of a pre‐metastatic niche formation. Conclusion: We demonstrated that B[a]P‐induced tumor exosomes can deliver circ_0011496 to activate miR‐486‐5p/TWF1/MMP9 cascade in the lung fibroblasts, generating a feedback loop that promoted HCC metastasis.

Background Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to limited treatment options and frequent resistance to targeted therapies. MET amplification is a promising therapeutic target in a subset of HCC. However, mechanisms of resistance to MET inhibitors are not fully understood, impeding the efficacy of treatments. Methods We performed a genome-wide CRISPR-Cas9 screen to identify genetic determinants of resistance to MET inhibitors. The efficacy of selective MET inhibitors, including capmatinib and tepotinib, was evaluated in MET-amplified HCC models. Mechanistic studies were conducted to characterize AKT signaling dynamics and tumour cell responses under various treatment conditions. Results MET inhibitors selectively suppressed tumour growth in MET-amplified HCC. However, PTEN deficiency sustained AKT activation despite MET blockade, facilitating tumour survival. Moreover, MET inhibitor treatment triggered adaptive upregulation of ERBB2/ERBB3, leading to AKT reactivation and resistance. Combined inhibition of MET and AKT or ERBB kinases synergistically restored therapeutic response and induced apoptosis. These resistance mechanisms also reduced the efficacy of cabozantinib. Notably, neither combination was effective in MET-high non-amplified HCC. Conclusion Our study identifies PTEN deficiency and ERBB2/ERBB3-mediated reactivation as key resistance mechanisms to MET inhibition in MET-amplified HCC. The findings support biomarker-informed combination strategies and underscore the importance of stratifying patients based on MET amplification status.

Background: This study aimed to investigate the critical factors associated with prognosis for children with hepatoblastoma (HB) in mainland China combined with the aspect of health economics and management. Methods: This study retrospectively reviewed children with HB in Renji Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine from January 2013 to December 2019. Descriptive analysis was used to describe the essential characteristics. Kaplan-Meier method and Cox proportional hazard models were used to estimate the survival rate and prognosis factors. Results: For the 87 children with HB, the average survival was 2,002.8 days (95% CI: 1,798.7–2,206.9 days), the 1- and 5-year survival rates were 87.7% and 78.9%, respectively. Undergoing surgery and sex were independent prognostic factors of childhood HB. Children with HB undergoing hepatectomy (HR: 0.039) or liver transplantation (HR: 0.142) had a better prognosis, while boys were associated with a poorer prognosis (HR: 3.614). The average medical expenses for childhood HB were 40,217.5±3,862.0 CNY and liver transplantation cost more than hepatectomy. Conclusions: The results had a comparable survival rate with other studies globally. Surgical therapy and sex are associated with the prognosis of children with HB. The economic burden of childhood HB deserves to be further explored.

Background: Missed or delayed child healthcare caused by the COVID-19 lockdown has threatened young children’s health and has had an unpredictable influence on caregivers’ child healthcare preferences. This study investigated caregivers’ child healthcare preferences and the factors that influence them among families with young children (0–3 years) during the lockdown in Shanghai. Methods: Participants in this cross-sectional study were enrolled through random encounter sampling. Questionnaires were distributed online from June 1 to November 10, 2022, in Shanghai. A total of 477 valid questionnaires were received. The demographics of caregivers and their families, children’s characteristics, COVID-19-related information, and caregivers’ healthcare preferences were analyzed. The statistical analyses included frequency and percentage, chi-square tests, and multinomial logistic regression. Results: Caregivers preferred child healthcare professionals in the community health service system (CHS; 47.6%) followed by hospital pediatricians (40.0%) during lockdown. Caregivers with the following characteristics preferred CHS: those with an annual household income of CNY 200,000–300,000, those whose youngest children were aged 8–12 months, and those who experienced early childhood physical development issues. Caregivers preferred hospitals if they had experienced healthcare-seeking-related difficulties in accessing professional guidance from hospital pediatricians. Conclusions: During pandemic lockdowns, policymakers should allocate more resources to CHS to meet caregivers’ childcare demands. Moreover, special attention should be given to the healthcare needs for CHS among families with specific demographics. Trial registration: Approval was obtained from the Ethics Committee of Shanghai Jiao Tong University School of Medicine School of Public Health (SJUPN-202,109; June 1, 2022).