Aberrant glycosaminoglycan biosynthesis by tumor suppressor EXTL2 deficiency promotes liver inflammation and tumorigenesis through Toll-like 4 receptor signaling.
Certain proteoglycans, consisting of a core protein and glycosaminoglycan (GAG) chains, are among the many types of biomolecules that can function as damage-associated molecular pattern molecules (DAMPs). We, therefore, hypothesized that the expression level and structural alteration of GAGs affect inflammation. We have previously reported that the effects on GAG biosynthesis caused by loss of the tumor suppressor gene exostosin-like 2 (Extl2) influence liver injury and regeneration processes. To examine how altered GAG biosynthesis may underscore the relationship between inflammation and tumorigenesis, we assessed its role in non-alcoholic steatohepatitis and hepatocarcinoma (HCC) induced by dietary obesity and insulin-resistance. We demonstrated that GAGs produced in the absence of EXTL2 act as DAMPs and directly input signals into cells via the Toll-like 4 receptor. In addition, the subsequent transcriptional activation of inflammatory and tumor-promoting cytokines by NF-κB contributes to injury- and inflammation-driven tumor promotion. Thus, dysregulated biosynthesis of GAGs is considered to increase the risk of HCC in a background of obesity and diabetes.
['Nadanaka|Satomi|S|', 'Hashiguchi|Taishi|T|', 'Kitagawa|Hiroshi|H|']
D000818:Animals D063646:Carcinogenesis D006528:Carcinoma, Hepatocellular D002460:Cell Line D002471:Cell Transformation, Neoplastic D006025:Glycosaminoglycans D006505:Hepatitis D007249:Inflammation D008099:Liver D008113:Liver Neoplasms D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D017351:N-Acetylglucosaminyltransferases D016328:NF-kappa B D065626:Non-alcoholic Fatty Liver Disease D011509:Proteoglycans D000067996:RAW 264.7 Cells D015398:Signal Transduction D051197:Toll-Like Receptor 4
glycosaminoglycan inflammation NF-kappaB (NF-κB) liver cancer proteoglycans (PG)