Zinc deficiency activates S100A8 inflammation in the absence of COX‐2 and promotes murine oral‐esophageal tumor progression

Autor: Xiuping Liu, Karl J. Smalley, Yubao Jiang, Cristian Taccioli, Hongping Chen, John L. Farber, Carlo M. Croce, Shaogui Wan, Kun Huang, Louise Y.Y. Fong
Rok vydání: 2010
Předmět:
Male
Cancer Research
Esophageal Neoplasms
Cox-2 null mice
4-Nitroquinoline 1-oxide
medicine.disease_cause
Dimethylnitrosamine
Mice
chemistry.chemical_compound
0302 clinical medicine
zinc deficiency
Mice
Knockout

0303 health sciences
4-Nitroquinoline-1-oxide
Tongue Neoplasms
3. Good health
Zinc
Oncology
030220 oncology & carcinogenesis
Disease Progression
Female
medicine.symptom
tongue cancer prevention
medicine.medical_specialty
S100A8 inflammation
Inflammation
Biology
03 medical and health sciences
Cyclin D1
Downregulation and upregulation
Stomach Neoplasms
Combination cancer therapy
Internal medicine
Cancer Genetics
medicine
Animals
Calgranulin A
030304 developmental biology
Cancer
transcriptome profiling
medicine.disease
Disease Models
Animal

Endocrinology
chemistry
Cyclooxygenase 2
Tumor progression
Carcinogens
Cancer research
Carcinogenesis
Gene Deletion
Zdroj: International Journal of Cancer. Journal International du Cancer
ISSN: 1097-0215
0020-7136
DOI: 10.1002/ijc.25688
Popis: Zinc (Zn)-deficiency (ZD) is implicated in the pathogenesis of human oral-esophageal cancers. Previously, we showed that in ZD mice genetic deletion of cyclooxygenase-2 (Cox-2) enhances N-nitrosomethylbenzylamine-induced forestomach carcinogenesis. By contrast, Cox-2 deletion offers protection in Zn-sufficient (ZS) mice. We hypothesize that ZD activates pathways insensitive to COX-2 inhibition, thereby promoting carcinogenesis. This hypothesis is tested in a Cox-2(-/-) mouse tongue cancer model that mimics pharmacologic blockade of COX-2 by firstly examining transcriptome profiles of forestomach mucosa from Cox-2(-/-) and wild-type mice on a ZD vs. ZS diet, and secondly investigating the roles of identified markers in mouse forestomach/tongue preneoplasia and carcinomas. In Cox-2(-/-) mice exposed to the tongue carcinogen 4-nitroquinoline 1-oxide, dietary ZD elicited tongue/esophagus/forestomach carcinomas that were prevented by ZS. The precancerous ZD:Cox-2(-/-) vs. ZS:Cox-2(-/-) forestomach had an inflammatory signature with upregulation of the proinflammation genes S100a8 and S100a9. Bioinformatics analysis revealed overrepresentation of inflammation processes comprising S100a8/a9 and an nuclear factor (NF)-κB network with connectivity to S100A8. Immunohistochemistry revealed co-overexpression of S100A8, its heterodimeric partner S100A9, the receptor for advanced glycation end-products (RAGE), NF-κB p65, and cyclin D1, in ZD:Cox-2(-/-) forestomach/tongue preneoplasia and carcinomas, evidence for the activation of a RAGE-S100A8/A9 inflammatory pathway. Accumulation of p53 in these carcinomas indicated activation of additional inflammatory pathways. Zn-replenishment in ZD:Cox-2(-/-) mice reversed the inflammation and inhibited carcinogenesis. Thus, ZD activates alternative inflammation-associated cancer pathways that fuel tumor progression and bypass the antitumor effect of Cox-2 ablation. These findings have important clinical implications, as combination cancer therapy that includes Zn may improve efficacy.
Databáze: OpenAIRE