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ALOX12: A Novel Insight in Bevacizumab Response, Immunotherapy Effect, and Prognosis of Colorectal Cancer

ABSTRACT: Colorectal cancer is a highly malignant cancer with poor prognosis and mortality rates. As the first biological agent approved for metastatic colorectal cancer (mCRC), bevacizumab was confirmed to exhibit good performance when combined with chemotherapy and immunotherapy. However, the efficacy of both bevacizumab and immunotherapy is highly heterogeneous across CRC patients with different stages. Thus, exploring a novel biomarker to comprehensively assess the prognosis and bevacizumab and immunotherapy response of CRC is of great significance. In our study, weighted gene co-expression network analysis (WGCNA) and the receiver operating characteristic (ROC) curves were employed to identify bevacizumab-related genes. After verification in four public cohorts and our internal cohort, ALOX12 was identified as a key gene related to bevacizumab response. Prognostic analysis and in vitro experiments further demonstrated that ALOX12 was closely associated with the prognosis, tumor proliferation, invasion, and metastasis. Multi-omics data analysis based on mutation and copy number variation (CNV) revealed that RYR3 drove the expression of ALOX12 and the deletion of 17p12 inhibited ALOX12 expression, respectively. Moreover, we interrogated the relationship between ALOX12 and immune cells and checkpoints. The results exhibited that high ALOX12 expression predicted a higher immune infiltration and better immunotherapy response, which was further validated in Tumor Immune Dysfunction and Exclusion (TIDE) and Subclass Mapping (SubMap) methods. Above all, our study provides a stable biomarker for clinical protocol optimization, prognostic assessment, precise treatment, and individualized treatment of CRC.

SUBMITTER: Weng S

PROVIDER: S-EPMC9271859 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Colorectal cancer (CRC) is the third most common cancer worldwide, in which aberrant activation of the RAS signaling pathway appears frequently. RAB proteins (RABs) are the largest Ras small GTPases superfamily that regulates intracellular membrane trafficking pathways. The dysregulation of RABs have been found in various diseases including cancers. Compared with other members of Ras families, the roles of RABs in colorectal cancer are less well understood. Methods: We analyzed the differential expression and clinicopathological association of RABs in CRC using RNA sequencing and genotyping datasets from TCGA samples. Moreover, the biological function of RAB17 and RAB34 were investigated in CRC cell lines and patient samples. Results: Of the 62 RABs we analyzed in CRC, seven (RAB10, RAB11A, RAB15, RAB17, RAB19, RAB20, and RAB25) were significantly upregulated, while six (RAB6B, RAB9B, RAB12, RAB23, RAB31, and RAB34) were significantly downregulated in tumor tissues as compared to normal. We found that the upregulated-RABs, which were highly expressed in metabolic activated CRC subtype (CMS3), are associated with cell cycle related pathways enrichment and positively correlated with the mismatch repair (MMR) genes in CRC, implying their role in regulating cell metabolism and tumor growth. While, high expression of the downregulated-RABs were significantly associated with poor prognostic CRC mesenchymal subtypes (CMS4), immune checkpoint genes, and tumor infiltrating immune cells, indicating their role in predicting prognosis and immunotherapy efficacy. Interestingly, though RAB34 mRNA is downregulated in CRC, its high expression is significantly associated with poor prognosis. In vitro experiments showed that RAB17 overexpression can promote cell proliferation via cell cycle regulation. While, RAB34 overexpression can promote cell migration and invasion and is associated with PD-L1/PD-L2 expression increase in CRC cells. Conclusions: Our study showed that RABs may play important roles in regulating cell cycle and immune-related pathways, therefore might be potential biomarkers in predicting prognosis and immunotherapy response in CRC.

Project description:BackgroundColorectal cancer (CRC) ranks among the most prevalent malignancies affecting the gastrointestinal tract. The infiltration of CD8+ T cells significantly influences the prognosis and progression of tumor patients.MethodsThis study establishes a CRC immune risk model based on CD8+ T cell-related genes. CD8+ T cell-related genes were identified through Weighted Gene Co-expression Network Analysis (WGCNA), and the enriched gene sets were annotated via Gene Ontology (GO) and Reactome pathway analysis. Employing machine learning methods, including the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm and Random Forest (RF), we identified nine genes associated with CD8+ T-cell infiltration. The infiltration levels of immune cells in CRC tissues were assessed using the ssGSEA algorithm.ResultsThese genes provide a foundation for constructing a prognostic model. The TCGA-CRC sample model's prediction scores were categorized, and the prediction models were validated through Cox regression analysis and Kaplan-Meier curve analysis. Notably, although CRC tissues with higher risk scores exhibited elevated levels of CD8+ T-cell infiltration, they also demonstrated heightened expression of immune checkpoint genes. Furthermore, comparison of microsatellite instability (MSI) and gene mutations across the immune subgroups revealed notable gene variations, particularly with APC, TP53, and TNNT1 showing higher mutation frequencies. Finally, the predictive model's efficacy was corroborated through the use of Tumor Immune Dysfunction and Exclusion (TIDE), Immune Profiling Score (IPS), and immune escape-related molecular markers. The predictive model was validated through an external cohort of CRC and the Bladder Cancer Immunotherapy Cohort. CLRN3 expression levels in tumor and adjacent normal tissues were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Subsequent in vitro and in vivo experiments demonstrated that CLRN3 knockdown significantly attenuated the malignant biological behavior of CRC cells, while overexpression had the opposite effect.ConclusionsThis study presents a novel prognostic model for CRC, providing a framework for enhancing the survival rates of CRC patients by targeting CD8+ T-cell infiltration.

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ALOX12: A Novel Insight in Bevacizumab Response, Immunotherapy Effect, and Prognosis of Colorectal Cancer

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