Identification and validation of roles of lysyl oxidases in the predictions of prognosis, chemotherapy and immunotherapy in glioma

Abstract

Background: Previous investigations have illustrated that lysyl oxidase family enzymes (LOXs) are contributing factors for tumor progression and remodeling immunomicroenvironment. However, it is scarce regarding comprehensive analysis of LOXs in the predictions of prognosis, chemotherapy and immunotherapy in glioma, the highly invasive brain tumor. Our present work aimed to explore the prognostic value, chemotherapeutic drug sensitivity and immunotherapy according to distinct LOXs expressions in glioma through bioinformatics analysis and experimental verification.Methods: We collected gene expression data and clinical characteristics from the public databases including Chinese Glioma Genome Atlas (CGGA)-325, CGGA-693, the Cancer Genome Atlas (TCGA), IMvigor210 and Van Allen 2015 cohorts. The correlations between the clinicopathological factors and differential LOXs expressions were analyzed. The ROC curve and Kaplan-Meier analysis were conducted to evaluate the prediction ability of prognosis. Chemotherapeutic drug sensitivity via distinct LOXs expression levels was predicted using the pRRophetic package. Immune score, immune cell infiltration and immune checkpoint expression levels were also analyzed through diverse algorithms in R software. Finally, mRNA and protein expressions of LOXs were validated in glioma cells (T98G and A172) by real-time quantitative PCR and Western blot, respectively.Results: Our results demonstrated that high levels of LOXs expressions were positively associated with glioma grades, older age and MGMT unmethylated status while elevations of LOXs were negatively correlated with IDH mutation or 1p/19q co-deletion. Furthermore, the glioma patients with low levels of LOXs also exhibited better prognosis. Also, differential LOXs expressions were associated with at least 12 chemotherapeutic drug sensitivity. Besides, it was also found that glioma patients with high LOXs expressions showed higher enrichment scores for immune cell infiltration and increased levels of immune checkpoints, suggesting the critical role of distinct LOXs expression levels for glioma immunotherapy. The predictive roles of LOXs expression in tumor immunotherapy were also validated in two immunotherapy cohorts including IMvigor 210 and Van Allen 2015. Experimental results revealed that expressions of LOX, LOXL1, LOXL2, and LOXL3 were higher in glioma cell lines at mRNA and protein levels.Conclusion: Our findings altogether indicate that LOXs have potent predictive value for prognosis, chemotherapy and immunotherapy in glioma patients.

Lysyl oxidase-like 1 predicts the prognosis of patients with primary glioblastoma and promotes tumor invasion via EMT pathway

“…A poor prognosis was found for GBM patients with high Lox expression in the TCGA cohort ( P = 0.044) but not in the CGGA cohort ( P = 0.067). These results were partially consistent with those of previous studies ( Han et al, 2014 ; Huang et al, 2018 ; Patnam et al, 2022 ; Xia et al, 2022 ). They reported the independent prognostic role of Lox in lower-grade glioma, suggesting that the prognostic value of Lox is related to the grade of glioma.…”

“…The expression of Loxl1 is significantly related to the antiapoptotic effects and migration of glioma cells ( Li et al, 2018 ; Yu et al, 2020 ). Consistent with our results, previous studies have indicated a similar prognostic role for Loxl1 in glioma using a single Kaplan‒Meier analysis ( Xia et al, 2022 ; Yu et al, 2020 ). In this study, we further included more clinicopathological factors and performed further Cox regression analyses in multiple GBM cohorts.…”

The entanglement of extracellular matrix molecules and immune checkpoint inhibitors in cancer: a systematic review of the literature

“…As mentioned before, ECM stiffness and structural organization are strongly regulated by the activity of LOX enzyme family, which includes LOX and LOX-like (LOXL) 1-4 ( 23 ). Due to their involvement in different processes, as linking bi-directionally the ECM and acting directly on the activation of signaling pathways regulating cancer cell survival, proliferation and differentiation, LOXs have been identified as pivotal factors in the formation and progression of different tumor types as glioma, gastric and endometrial carcinoma ( 130 – 133 ). Among the LOX family of enzymes, LOXL3 has also been shown to play immunomodulatory functions in the TME.…”

Identification of key genes CCL5, PLG, LOX and C3 in clear cell renal cell carcinoma through integrated bioinformatics analysis

“…LOX expression was associated with lymph node metastasis, distant tumor metastasis and poor prognosis in GC patients, and the integrated analysis supported LOX as a speci c diagnostic and prognostic biomarker for GC patients (Jia et al 2022). In addition, LOX has an excellent predictive value for chemotherapy, immunotherapy and prognosis in patients with glioma (Xia et al 2022). Few studies are available concerning LOX in ccRCC.…”