Biomedical subjects

Cong Zhang

Publications and source records attributed to Cong Zhang.

3 recordsLinked to original sources

PubMed2026

Genetic regulation of CPEB3-mediated alternative polyadenylation associated with survival of patients with hepatocellular carcinoma.

BACKGROUND: Alternative polyadenylation (APA) is a key post-transcriptional mechanism that regulates gene expression by modulating 3'UTR length, its dysregulation has been implicated in carcinogenesis. How genetic variants influence APA to affect hepatocellular carcinoma (HCC) prognosis remains unclear. METHODS: Prognosis-APA quantitative trait loci (apaQTL) were performed using genotype and APA profiling from TCGA data. A two-stage survival analysis in 848 Chinese and 369 TCGA LIHC patients and functional validation were used to identify prognostic apaQTL in HCC progression. RESULTS: A total of 2,025 and 817 significant APA events were identified in Chinese and TCGA cohort, respectively. Besides, 859 events were associated with poor prognosis in HCC and enriched in RNA splicing / metabolism pathways. We detected 32,034 significant apaQTLs, predominantly enriched in 3'UTRs and RBP-binding regions. CPEB3 was prioritized as a key APA regulator RBP; its low expression correlated with poor patient survival and promoted proliferation, migration, and invasion in HCC cells. Notably, a functional apaQTL variant rs2037547, located in GSK3B and mediated by CPEB3, demonstrated a poor survival of HCC patients in both cohort (pooled HR=1.29, p=0.016). Mechanistically, rs2037547 promoted aberrant APA at proximal poly(A) sites of GSK3B through CPEB3, leading to increased expression of short 3'UTR isoform. This regulatory alteration enhanced HCC cell proliferation, invasion, and migration, and contributed to HCC progression. CONCLUSION: These findings elucidated the distinct role of apaQTL-mediated APA dysregulation in HCC prognosis, providing insights for prognostic stratification and potential targets for personalized therapy in HCC.

RNA-binding proteins↗

PubMed2026

USP10-SIRT6-PARP1 axis drives keratinocyte senescence and skin photoaging under chronic UVA exposure.

Chronic exposure to ultraviolet A (UVA) radiation is the principal environmental driver of skin photoaging, yet the upstream molecular events that commit irradiated keratinocytes to senescence remain poorly understood. Here we show that SIRT6, an NAD+-dependent protein deacetylase with established roles in genome maintenance and organismal longevity, functions as a central gatekeeper of keratinocyte homeostasis under photic stress. Using a chronic UVA irradiation model in mice together with cultured human keratinocytes, we demonstrate that UVA inflicts extensive DNA damage and G2/M cell-cycle arrest, accompanied by selective depletion of SIRT6 among all sirtuin family members. Mechanistically, UVA suppresses the deubiquitinase USP10 at both transcriptional and post-transcriptional levels, thereby licensing ubiquitin-dependent proteasomal degradation of SIRT6. The resulting SIRT6 deficiency unleashes hyperactivation of the DNA-damage sensor PARP1, amplifying genomic injury signaling and driving keratinocytes into irreversible senescence with concomitant elaboration of a broad pro-inflammatory secretory programme encompassing chemokines and cytokines. Pharmacological reactivation of SIRT6 with the selective agonist UBCS039 reverses epidermal hyperplasia, attenuates DNA damage and senescence marker accumulation, and suppresses inflammatory mediator induction both in vivo and in vitro, establishing SIRT6 loss as a causal rather than correlative event. Furthermore, molecular docking and functional validation identify osthole, a plant-derived coumarin from the medicinal herb Cnidium monnieri, as a candidate SIRT6-engaging compound that counteracts UVA-induced senescence and inflammation in keratinocytes. Collectively, these findings define a USP10-SIRT6-PARP1 signaling axis whose disruption underlies cutaneous photoaging and suggest that SIRT6-directed strategies may offer therapeutic benefit against UV-driven tissue degeneration.

Animals↗

PubMed2026

Patient-derived organoids predict responses to chemotherapy and PARP inhibitors in advanced ovarian cancer.

BACKGROUND: While tumor organoids hold promise for personalized medicine, clinical validation of epithelial ovarian cancer (EOC) organoids as predictors of therapeutic efficacy-particularly for PARP inhibitors (PARPi)-remains unestablished. METHODS: Patient-derived organoids (PDOs) were established from treatment-naive EOC specimens and characterized by H&E staining, immunohistochemistry, and whole-exome sequencing. Drug sensitivity testing (DST) was performed using carboplatin, paclitaxel, and PARPi (olaparib and niraparib). Clinical homologous recombination deficiency (HRD) status was assessed by tumor sequencing. Organoid responses were prospectively compared to patient outcomes after first-line chemotherapy (carboplatin/paclitaxel) and PARPi maintenance. RESULTS: PDOs were successfully established from 21 of 30 patients (70%) across multiple EOC subtypes and preserved the histopathological features and genomic landscapes of their corresponding primary tumors. Organoid-based DST accurately predicted responses to first-line carboplatin/paclitaxel, with a sensitivity of 100% (95% CI 62.88-100%), specificity of 66.67% (95% CI 12.53-98.23%), accuracy of 91.67% (95% CI 61.52-99.79%), AUC of 0.95 (95% CI 0.85-1.00), and Cohen's kappa of 0.75 (95% CI 0.30-1.00). In evaluating PARPi response, organoids revealed discrepancies between genomic HRD status and actual drug responses. One HRD-positive PDO was PARPi-resistant, consistent with patient non-response, while two HRR-proficient PDOs showed PARPi sensitivity and corresponding clinical benefit. CONCLUSIONS: EOC-derived PDOs provide a robust platform for predicting chemotherapy response and offer added value in assessing PARPi efficacy beyond genomic profiling. Combination of organoid-based testing with genomic analysis may improve precision treatment strategies in EOC.

Humans↗