Cancer letters最新文献

MATR3 is a nuclear matrix protein implicated in various cancers; however, its specific role in tumor progression remains unclear. The study utilized the TCGA database to reveal that MATR3 expression is upregulated in liver cancer and is correlated with poor prognosis. Functionally, MATR3 promoted liver cancer cell proliferation and metastasis. Comprehensive RNA sequencing analysis showed that MATR3 significantly affected the type I IFN signaling pathway and DHX58 is a downstream target of MATR3. Further experiments showed that MATR3 bound to DHX58 mRNA through its RRM structural domain and recruited YTHDF2, an m⁶A reader, leading to degradation of DHX58 mRNA and suppression of the type I IFN signaling pathway. The knockout of MATR3 in liver cancer cells triggered a natural immune response that stimulated CD8⁺ T cells to eliminate liver cancer cells. This study demonstrated that MATR3 downregulates type I IFN signaling in liver cancer cells through m⁶A modification and inhibits immune cell infiltration within tumors. These findings expand our understanding of the role of MATR3 in liver cancer.

KRAS^G12D mutation-driven pancreatic ductal adenocarcinoma (PDAC) represents a major challenge in medicine due to late diagnosis and treatment resistance. Here, we report that macroautophagy (hereafter autophagy), a cellular degradation and recycling process, contributes to acquired resistance against novel KRAS^G12D-targeted therapy. The KRAS^G12D protein inhibitor MRTX1133 induces autophagy in KRAS^G12D-mutated PDAC cells by blocking MTOR activity, and increased autophagic flux prevents apoptosis. Mechanistically, autophagy facilitates the generation of glutamic acid, cysteine, and glycine for glutathione synthesis. Increased glutathione levels reduce reactive oxygen species production, which impedes CYCS translocation from mitochondria to the cytosol, ultimately preventing the formation of the APAF1 apoptosome. Consequently, genetic interventions (utilizing ATG5 or BECN1 knockout) or pharmacological inhibition of autophagy (with chloroquine, bafilomycin A₁, or spautin-1) enhance the anticancer activity of MRTX1133 in vitro and in various animal models (subcutaneous, patient-derived xenograft, and orthotopic). Moreover, the release of histones by apoptotic cells triggers an adaptive immune response when combining an autophagy inhibitor with MRTX1133 in immunocompetent mice. These findings establish a new strategy to overcome KRAS^G12D-targeted therapy resistance by inhibiting autophagy-dependent glutathione synthesis.

As the most abundant post-transcriptional modification in eukaryotes, N⁶-methyladenosine (m⁶A) plays a crucial role in cancer cell proliferation, invasion and chemoresistance. However, its specific effects on chemosensitivity to oxaliplatin-based regimens and the impact of these drugs on m⁶A methylation levels in colorectal cancer (CRC) remain largely unexplored. In this study, we demonstrated that the m⁶A methyltransferase Wilms tumor 1-associating protein (WTAP) weakens oxaliplatin chemosensitivity in HCT116 and DLD1 cells. Mechanistically, oxaliplatin treatment upregulated WTAP expression, preventing multiple forms of cell death simultaneously, a process known as PANoptosis, by decreasing intracellular oxidative stress through maintaining the expression of nuclear factor erythroid-2-related factor 2 (NRF2), a major antioxidant response element, in an m⁶A-dependent manner. In addition, high WTAP expression in CRC patients is associated with a poor prognosis and reduced benefit from standard chemotherapy by clinical data analysis of The Cancer Genome Atlas (TCGA) database and patient cohort study. These findings suggest that targeting WTAP-NRF2-PANoptosis axis could enhance the antitumor efficacy of oxaliplatin-based chemotherapy in CRC treatment.

Nuclear Bcl-xL is found to promote cancer metastasis independently of its mitochondria-based anti-apoptotic activity. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates histone H3 trimethyl Lys4 (H3K4me3) modification have yet to be understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds to Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced invasion and metastasis in mouse models. Furthermore, knockout of CtBP2 not only reduces the nuclear portion of Bcl-xL but also suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of the MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGFβ mRNA upregulation, as well as invasion. Moreover, the cleavage under targets and release using nuclease (CUT&RUN) assay coupled with next-generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor regions of genes encoding TGFβ and its signaling pathway members in cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1 and this study offers new therapeutic strategies to treat Bcl-xL-overexpressing cancer.

Immunotherapy, remarkably immune checkpoint inhibitors (ICIs), has significantly altered the treatment landscape for non-small cell lung cancer (NSCLC). Despite their success, the discontinuation of ICIs therapy may occur due to factors such as prior treatment completion, disease progression during ICIs treatment, or immune-related adverse events (irAEs). As numerous studies highlight the dynamic nature of immune responses and the sustained benefits of ICIs, ICIs rechallenge has become an attractive and feasible option. However, the decision-making process for ICIs rechallenge in clinical settings is complicated by numerous uncertainties. This review systematically analyses existing clinical research evidence, classifying ICIs rechallenge into distinct clinical scenarios, exploring methods to overcome ICIs resistance in rechallenge instances, and identifying biomarkers to select patients likely to benefit from rechallenge. By integrating recent studies and new technologies, we offer crucial recommendations for future clinical trial design and provide a practical guideline to maximize the therapeutic benefits of immunotherapy for NSCLC patients.

This study evaluated the cellular heterogeneity and molecular mechanisms of hepatocellular carcinoma (HCC). Single cell RNA sequencing (scRNA-seq), transcriptomic data, histone lactylation-related genes were collected from public databases. Cell-cell interaction, trajectory, pathway, and spatial transcriptome analyses were executed. Differential expression and survival analyses were conducted. Western blot, Real-time reverse transcription PCR (qRT-PCR), and Cell Counting Kit 8 (CCK8) assay were used to detect the expression of αSMA, AKR1B10 and its target genes, and verify the roles of AKR1B10 in HCC cells. Hepatic stellate cell (HSC) subgroups strongly interacted with tumor cell subgroups, and their spatial distribution was heterogeneous. Two candidate prognostic genes (AKR1B10 and RMRP) were obtained. LONP1, NPIPB3, and ZSWIM6 were determined as AKR1B10 targets. Besides, the expression levels of AKR1B10 and αSMA were significantly increased in LX-2 + HepG2 and LX-2 + HuH7 groups compared to those in LX-2 group, respectively. sh-AKR1B10 significantly inhibited the HCC cell proliferation and change the expression of AKR1B10 target genes, Bcl-2, Bax, Pan Kla, and H3K18la at protein levels. Our findings unveil the pivotal role of HSCs in HCC pathogenesis through regulating histone lactylation.