PMID- 35768785 OWN - NLM STAT- MEDLINE DCOM- 20220701 LR - 20220716 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 22 IP - 1 DP - 2022 Jun 29 TI - 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. PG - 714 LID - 10.1186/s12885-022-09722-x [doi] LID - 714 AB - 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. CI - (c) 2022. The Author(s). FAU - Li, Jing AU - Li J AD - Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China. AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong feng Road East, Guangzhou, 510060, China. FAU - Tang, Ling-Long AU - Tang LL AD - Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China. AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong feng Road East, Guangzhou, 510060, China. FAU - Ma, Jun AU - Ma J AD - Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China. majun2@mail.sysu.edu.cn. AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong feng Road East, Guangzhou, 510060, China. majun2@mail.sysu.edu.cn. LA - eng PT - Journal Article DEP - 20220629 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Cornified Envelope Proline-Rich Proteins) RN - 0 (SPRR1A protein, human) RN - EC 1.13.11.31 (ALOX12B protein, human) RN - EC 1.13.11.31 (Arachidonate 12-Lipoxygenase) SB - IM EIN - BMC Cancer. 2022 Jul 11;22(1):755. PMID: 35820802 MH - *Arachidonate 12-Lipoxygenase/genetics/metabolism MH - *Cornified Envelope Proline-Rich Proteins/metabolism MH - DNA Damage MH - *DNA Repair MH - *Head and Neck Neoplasms/genetics/virology MH - *Human papillomavirus 16/isolation & purification MH - Humans MH - *Papillomavirus Infections/genetics/pathology/virology MH - Prognosis MH - *Squamous Cell Carcinoma of Head and Neck/genetics/virology MH - Tumor Microenvironment/genetics PMC - PMC9241267 OTO - NOTNLM OT - Cancer-associated fibroblasts OT - DNA damage response OT - Head and neck squamous cell carcinoma OT - Human papilloma virus 16-negative OT - Tumor microenvironment COIS- The authors declare that they have no competing interests. EDAT- 2022/06/30 06:00 MHDA- 2022/07/02 06:00 PMCR- 2022/06/29 CRDT- 2022/06/29 23:39 PHST- 2021/12/09 00:00 [received] PHST- 2022/05/30 00:00 [accepted] PHST- 2022/06/29 23:39 [entrez] PHST- 2022/06/30 06:00 [pubmed] PHST- 2022/07/02 06:00 [medline] PHST- 2022/06/29 00:00 [pmc-release] AID - 10.1186/s12885-022-09722-x [pii] AID - 9722 [pii] AID - 10.1186/s12885-022-09722-x [doi] PST - epublish SO - BMC Cancer. 2022 Jun 29;22(1):714. doi: 10.1186/s12885-022-09722-x.