Cancer Cell International最新文献

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant liver tumor with poor clinical outcomes. Accumulated evidence has demonstrated lactylation plays a vital role in the metabolic reprogramming. However the mechanisms underlying the role of lactylation in the regulation of HCC progression remain largely unknown. This study aims to construct a prognostic model based on lactylation-related metabolism genes, and further explore its prognostic significance and biological function in HCC.

Methods: In this study, a robust prognostic prediction model has been constructed employing a complex machine learning framework using public bulk RNA-seq and proteomic HCC dataset. Moreover, the clinical application of this model was explored, and its biological functions were validated using several in vitro experiments. Subsequently, we performed functional analysis, survival analysis, tumor immune microenvironment analysis and drug sensitivity to demonstrate our model's potential in translational cancer medicine.

Results: We developed an integrative machine learning-based computational framework to generate a predictive Metabolism-related Lactylation Index (MRLI) within four independent HCC cohorts and validated its prognostic accuracy through various algorithms. Notably, compared to published gene signatures, MRLI demonstrated robust predictive capability. In addition, single-cell analysis demonstrated that the MRLI is predominantly localized within HCC cells and correlates with tumor malignancy. Mechanistically, Gene Set Enrichment Analysis (GSEA) suggested that the MRLI may be associated with cellular proliferation and metabolic reprogramming, which was further confirmed by experimental evidence. Subsequently, public spatial transcriptomics and bulk RNA-seq analysis revealing that the highly MRLI predicts a tumor immunosuppressive microenvironment, which was further verification in a cohort of 40 HCC samples by multiple immunofluorescence. Additionally, groups with highly MRLI showed decreased sensitivity to sorafenib, immune checkpoint inhibitors, and TACE, highlighting the potential of MRLI in facilitating personalized treatment strategies.

Conclusion: Our study has developed a novel MRLI as a predictive marker for prognosis and therapeutic outcomes in patients with HCC. These findings indicate that lactylation promotes malignant cell phenotypes and immune microenvironment remodeling partially through metabolic regulation, suggesting it as a potential clinical therapeutic target.

Background: Although androgen receptor (AR)-targeted therapies have shown notable clinical efficacy in prostate cancer (PCa), the emergence of drug resistance remains a critical factor driving the clinical prognosis in castration-resistant prostate cancer (CRPC). Aberrant tumor lipid metabolism not only fulfills the energetic and biosynthetic requirements of rapidly proliferating cancer cells but also contributes to the development of therapeutic resistance.

Methods: We examined SOX8 expression in enzalutamide resistance (EnzR) cell lines and validated its association with tumor progression and clinical outcome. The malignant phenotypes related to EnzR were assessed in vitro using PCa cell lines with stable SOX8 overexpression or knockdown. Tumor xenografts were subsequently generated by inoculating the corresponding cell lines into nude mice. To elucidate the underlying mechanisms, we conducted RNA-seq, CUT&Tag, non-targeted metabolomics, and a series of molecular and biochemical assays.

Results: SOX8 expression was elevated in EnzR prostate cancer cell lines and positively correlated with poor patient prognosis. Reduced SOX8 expression enhanced cellular sensitivity to enzalutamide, whereas elevated SOX8 expression decreased drug responsiveness. Chromatin immunoprecipitations (ChIP) assays revealed that AR was enriched at the SOX8 promoter region and transcriptionally repressed SOX8. In vivo, stable SOX8 knockdown markedly suppressed tumor growth in nude mouse xenografts. Mechanistically, SOX8 promotes the EnzR by reprograming lipid metabolism and we identified carnitine palmitoyltransferase 2 (CPT2), a key enzyme in lipid metabolism, as a novel downstream target of SOX8. SOX8-driven lipid metabolic reprogramming promoted enzalutamide resistance through the SOX8/CPT2 axis.

Conclusions: High SOX8 expression promotes EnzR in PCa, suggesting SOX8 as a potential therapeutic target. Our findings demonstrate that SOX8 drives EnzR by activating the SOX8/CPT2 axis, thereby inducing lipid metabolic reprogramming in PCa cells.