Survival-related indicators ALOX12B and SPRR1A are associated with DNA damage repair and tumor microenvironment status in HPV 16-negative head and neck squamous cell carcinoma patients

Abstract

Objectives To investigate prognostic-related gene signature based on DNA damage repair and tumor microenvironment statue in human papillomavirus 16 negative (HPV16-) head and neck squamous cell carcinoma (HNSCC). Methods For the RNA-sequence matrix in HPV16- HNSCC in the Cancer Genome Atlas (TCGA) cohort, the DNA damage response (DDR) and tumor microenvironment (TM) status of each patient sample was estimated by using the ssGSEA algorithm. Through bioinformatics analysis in DDR_high/TM_high (n = 311) and DDR_high/TM_low (n = 53) groups, a survival-related gene signature was selected in the TCGA cohort. Two independent external validation cohorts (GSE65858 (n = 210) and GSE41613 (n = 97)) with HPV16- HNSCC patients validated the gene signature. Correlations among the clinical-related hub differentially expressed genes (DEGs) and infiltrated immunocytes were explored with the TIMER2.0 server. Drug screening based on hub DEGs was performed using the CellMiner and GSCALite databases. The loss-of-function studies were used to evaluate the effect of screened survival-related gene on the motility of HPV- HNSCC cells in vitro. Results A high DDR level (P = 0.025) and low TM score (P = 0.012) were independent risk factors for HPV16- HNSCC. Downregulated expression of ALOX12B or SPRR1A was associated with poor survival rate and advanced cancer stages. The pathway enrichment analysis showed the DDR_high/TM_low samples were enriched in glycosphingolipid biosynthesis-lacto and neolacto series, glutathione metabolism, platinum drug resistance, and ferroptosis pathways, while the DDR_high/TM_low samples were enriched in Th17 cell differentiation, Neutrophil extracellular trap formation, PD − L1 expression and PD − 1 checkpoint pathway in cancer. Notably, the expression of ALOX12B and SPRR1A were negatively correlated with cancer-associated fibroblasts (CAFs) infiltration and CAFs downstream effectors. Sensitivity to specific chemotherapy regimens can be derived from gene expressions. In addition, ALOX12B and SPRR1A expression was associated with the mRNA expression of insulin like growth factor 1 receptor (IGF1R), AKT serine/threonine kinase 1 (AKT1), mammalian target of rapamycin (MTOR), and eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) in HPV negative HNSCC. Down-regulation of ALOX12B promoted HPV- HNSCC cells migration and invasion in vitro. Conclusions ALOX12B and SPRR1A served as a gene signature for overall survival in HPV16- HNSCC patients, and correlated with the amount of infiltrated CAFs. The specific drug pattern was determined by the gene signature.

The mast cell reaction in premalignant and malignant lesions of the head and neck

“…MC tryptase is expressed as a basic marker by all MCs, and MC chymase is expressed only by a subclass of MCs [ 13 ]. This aspect confirms once again the heterogeneity of this cell population, but it is the support to identify them with a highly specific method [ 14 ]. The MCs have been identified in tumors of the oral cavity and head and neck a long time ago.…”

Fatty acids metabolism affects the therapeutic effect of anti-PD-1/PD-L1 in tumor immune microenvironment in clear cell renal cell carcinoma

“…Arachidonate 12-lipoxygenase, 12R type (ALOX12B) can convert arachidonic acids to 12R-hydroxyeicosatetraenoic acids 8 and is responsible for immune activity blocking the uptake of apoptotic cells through inflammatory monocytes which reduces antigen presentation to T cells in tumor [ 44 ]. Downregulation of ALOX12B prompts poor survival rate and advanced stages negative HPV 16-negative head and neck squamous cell carcinoma [ 45 ]. Arachidonate 15-lipoxygenase, type B (ALOX15B) upregulated in RCC-infiltrating macrophages, mediates lipid metabolism in TAMs and contributes to tumor progression as well as tumor immunity [ 46 , 47 ].…”

Spatial tissue proteomics reveals distinct landscapes of heterogeneity in cutaneous papillomavirus‐induced keratinocyte carcinomas

“…80 Increased expression of TGM3 and SPRR1A in MnPV-induced tumors may account for their low level of aggressiveness similar to other cancer types. 81,82 Reducing COL1A1 levels in MnPV-infected tissue (Figure 5E) may have the same purpose, as increased expression of COL1A1, as well as COL1A2, were previously associated with lower survival of ovarian cancer patients. 83 However, diminished CAV1 levels in MnPVinduced tumors (data set 1, log2FC = -1.32 [Supporting Information: STable 3]; data set 2, log2FC = -4.56 [Supporting Information:…”

“…Transglutaminase 3 (TGM3), one of the top upregulated proteins, catalyzes the crosslinking of different structural envelope proteins, 79 for example, the strongly upregulated SPRR1A (Figure 5E), during terminal differentiation 80 . Increased expression of TGM3 and SPRR1A in MnPV‐induced tumors may account for their low level of aggressiveness similar to other cancer types 81,82 . Reducing COL1A1 levels in MnPV‐infected tissue (Figure 5E) may have the same purpose, as increased expression of COL1A1 , as well as COL1A2 , were previously associated with lower survival of ovarian cancer patients 83 .…”