New perspectives in prognostication of hepatocellular carcinoma: The role and clinical implications of transient receptor potential family genes.

The study titled "Transient receptor potential-related risk model predicts prognosis of hepatocellular carcinoma patients" is a significant contribution to hepatocellular carcinoma (HCC) research, highlighting the role of transient receptor potential (TRP) family genes in the disease's progression and prognosis. Utilizing data from The Cancer Genome Atlas database, it establishes a new risk assessment model, emphasizing the interaction of TRP genes with tumor proliferation pathways, key metabolic reactions like retinol metabolism, and the tumor immune microenvironment. Notably, the overexpression of the TRPC1 gene in HCC correlates with poorer patient survival outcomes, suggesting its potential as a prognostic biomarker and a target for personalized therapy, particularly in strategies combining immunotherapy and anti-TRP agents.

WTAP-induced N6-methyladenosine of PD-L1 blocked T-cell-mediated antitumor activity under hypoxia in colorectal cancer.

N6-Methyladenosine (m6A) is a important process regulating gene expression post-transcriptionally. Programmed death ligand 1 (PD-L1) is a major immune inhibitive checkpoint that facilitates immune evasion and is expressed in tumor cells. In this research we discovered that Wilms' tumor 1-associated protein (WTAP) degradation caused by ubiquitin-mediated cleavage in cancer cells (colorectal cancer, CRC) under hypoxia was inhibited by Pumilio homolog 1 (PUM1) directly bound to WTAP. WTAP enhanced PD-L1 expression in a way that was m6A-dependent. m6A "reader," Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) identified methylated PD-L1 transcripts and subsequently fixed its mRNA. Additionally, we found that T-cell proliferation and its cancer cell-killing effects were prevented by overexpression of WTAP in vitro and in vivo. Overexpression prevented T cells from proliferating and killing CRC by maintaining the expression of PD-L1. Further evidence supporting the WTAP-PD-L1 regulatory axis was found in human CRC and organoid tissues. Tumors with high WTAP levels appeared more responsive to anti-PD1 immunotherapy, when analyzing samples from patients undergoing treatment. Overall, our findings demonstrated a novel PD-L1 regulatory mechanism by WTAP-induced mRNA epigenetic regulation and the possible application of targeting WTAP as immunotherapy for tumor hypoxia.

Up-regulation of PUM1 by miR-218-5p promotes colorectal tumor-initiating cell properties and tumorigenesis by regulating the PI3K/AKT axis.

Background: Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Advanced stage CRC, during the recent past, had a dismal prognosis and only a few available treatments. Pumilio homologous protein 1 (PUM1) is reportedly aberrant in human malignancies, including CRC. However, the role of PUM1 in the regulation of tumor-initiating cells (T-ICs) remains unknown. Methods: The levels of messenger RNAs (mRNAs) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunoblot analyses. Statistical analyses were performed to determine the associations between the levels of PUM1 and tumor features and patient outcomes. Whether PUM1 is a downstream target of miR-218-5p was verified by bioinformatics target gene prediction and qRT-PCR. Results: Herein, it was found that T-ICs, chemoresistance, and recurrent CRC samples all manifest increased PUM1 expression. Functional investigations have shown that PUM1 increased the self-renewal, tumorigenicity, malignant proliferation, and chemoresistance of colorectal cells. PUM1 activates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway biochemically. Furthermore, it was discovered that miR-218-5p specifically targets T-ICs' PUM1 3'-untranslated region (3'-UTR). More importantly, the PUM1/PI3K/AKT axis regulates CRC cells' responses to treatment with cetuximab, and PUM1 overexpression increased cetuximab resistance. More evidence points to the possibility that low PUM1 may predict cetuximab benefits in CRC patients after analysis of the patient cohort, patient-derived tumor organoids, and patient-derived xenografts (PDXs). Conclusions: Taken together, the result of this work points to the critical function of the miR-218-5p/PUM1/PI3K/AKT regulatory circuit in regulating T-ICs characteristics and thus suggests possible therapeutic targets for CRC.

Development and validation of an epithelial-mesenchymal transition-related gene signature for predicting prognosis.

BACKGROUND: Currently, there are many therapeutic methods for lung adenocarcinoma (LUAD), but the 5-year survival rate is still only 15% at later stages. Epithelial- mesenchymal transition (EMT) has been shown to be closely associated with local dissemination and subsequent metastasis of solid tumors. However, the role of EMT in the occurrence and development of LUAD remains unclear. AIM: To further elucidate the value of EMT-related genes in LUAD prognosis. METHODS: Univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses were applied to establish and validate a new EMT-related gene signature for predicting LUAD prognosis. The risk model was evaluated by Kaplan-Meier survival analysis, principal component analysis, and functional enrichment analysis and was used for nomogram construction. The potential structures of drugs to which LUAD is sensitive were discussed with respect to EMT-related genes in this model. RESULTS: Thirty-three differentially expressed genes related to EMT were found to be highly associated with overall survival (OS) by using univariate Cox regression analysis (log2FC ≥ 1, false discovery rate < 0.001). A prognostic signature of 7 EMT-associated genes was developed to divide patients into two risk groups by high or low risk scores. Kaplan-Meier survival analysis showed that the OS of patients in the high-risk group was significantly poorer than that of patients in the low-risk group (P < 0.05). Multivariate Cox regression analysis showed that the risk score was an independent risk factor for OS (HR > 1, P < 0.05). The results of receiver operator characteristic curve analysis suggested that the 7-gene signature had a perfect ability to predict prognosis (all area under the curves > 0.5). CONCLUSION: The EMT-associated gene signature classifier could be used as a feasible indicator for predicting OS.