SEMA6B Overexpression Predicts Poor Prognosis and Correlates With the Tumor Immunosuppressive Microenvironment in Colorectal Cancer

Abstract

Background: Semaphorin 6b (SEMA6B) is a member of the semaphorin axon-guidance family and has been demonstrated to both induce and inhibit tumor progression. However, the role of SEMA6B in colorectal cancer (CRC) has remained unclear. This study sought to explore the promising prognostic biomarker for CRC and to understand the expression pattern, clinical significance, immune effects, and biological functions of SEMA6B.Methods: SEMA6B expression in CRC was evaluated via multiple gene and protein expression databases and we identified its prognostic value through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Correlations between SEMA6B expression and components of the tumor immune microenvironment were analyzed by packages implemented in R, Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), and Tumor-Immune System Interactions database (TISIDB). RNA interference was performed to silence the expression of SEMA6B to explore its biological roles in the colon cancer cell lines HCT116 and LoVo.Results: The messenger RNA (mRNA) level of SEMA6B and the protein expression were higher in CRC tissues than adjacent normal tissues from multiple CRC datasets. High SEMA6B expression was significantly associated with dismal survival. Multivariate Cox regression analysis demonstrated that SEMA6B was an independent prognostic factor for progression-free survival (PFS). The nomogram showed a favorable predictive ability in PFS. Functional enrichment analysis and the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm revealed that the gene cluster associated with the high SEMA6B group were prominently involved in immune responses and inflammatory activities. Notably, SEMA6B expression was positively correlated with infiltrating levels of CD4+ T cells, macrophages, myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), neutrophils, and dendritic cells. Moreover, SEMA6B expression displayed strong correlations with diverse marker sets of immunosuppressive cells in CRC. Integrative analysis revealed that immunosuppressive molecules and immune checkpoints were markedly upregulated in CRC samples with high SEMA6B expression. Furthermore, knockdown of SMEA6B in colon cancer cells significantly inhibited cell proliferation, migration, invasion and reduced the mRNA levels of immunosuppressive molecules.Conclusion: Our findings provide evidence that high SEMA6B expression correlated with adverse prognosis and the tumor immunosuppressive microenvironment in CRC patients. Therefore, SEMA6B may serve as a novel prognostic biomarker for CRC, which offers further insights into developing CRC-targeted immunotherapies.

Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy

“…Family with sequence similarity 111 member B (FAM111B) is a 16 kb gene situated on human chromosome 11q12.1, which has shown functions in various cancer types, including thyroid cancer, pancreatic adenocarcinoma, lung cancer, and cervical cancer ( 41 – 44 ). Semaphorin 6b (SEMA6B) promotes and suppresses tumor progression ( 45 ). In our analysis, SEMA6B was shown to contribute to the development of THCA.…”

Computed tomography-detected extramural venous invasion-related gene signature: a potential negative biomarker of immune checkpoint inhibitor treatment in patients with gastric cancer

“…Based on how the EMVI score gene signature functions, the mechanism of CT-detected EMVI may be associated with immunology and angiogenesis, which accords with the immune-vascular cross-talk mechanism [ 30 ]. SEMA6B has also been shown to correlate with tumor invasion and metastasis in GC [ 31 ] and to be closely related to the immunosuppressive microenvironment in colorectal cancer [ 32 ].…”

Developing an m5C regulator–mediated RNA methylation modification signature to predict prognosis and immunotherapy efficacy in rectal cancer

“…TIDE is a reliable surrogate biomarker that could accurately predict immune checkpoint blockade (ICB) response by measuring the tumor immune escape, and it even performed better than PD-L1 expression in melanoma; that is, a higher TIDE score is associated with worse ICB response and worse patient survival under anti-PD1 and anti-CTLA4 therapies (90). According to our previous studies and others, the immune landscape is crucial in assessing the efficacy of immunotherapy and chemotherapy targeting CRC patients (91)(92)(93)(94). However, the role of m 5 C RNA methylation regulators in patients with rectal cancer is still unclear.…”