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Roles of Fibulin-2 in Carcinogenesis.

ABSTRACT: Fibulin-2, an extracellular matrix (ECM) protein expressed in normal epithelia, is a kind of fibulin which is associated with basement membranes (BM) and elastic ECM fibers. The role of fibulin-2 has been recognized as an oncogene. The upregulation of fibulin-2 correlates with cancer development and progression. Furthermore, the upregulation of fibulin has been detected in ovarian cancer and stomach adenocarcinoma. However, the downregulation of fibulin has been detected in different intestinal and respiratory tumor cells. Additional studies have revealed that the role of fibulin-2 in carcinogenesis is context dependent and is caused by the interaction of fibulin proteins such as cell surface receptors and other ECM proteins, including integrins and syndecans. The present study summarizes the role of fibulin in carcinogenesis and its underlying molecular mechanism.

SUBMITTER: Zhang H

PROVIDER: S-EPMC6977632 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Roles of Fibulin-2 in Carcinogenesis.

Zhang Huayue H Hui Dengcheng D Fu Xiaoling X

Medical science monitor : international medical journal of experimental and clinical research 20200109

Fibulin-2, an extracellular matrix (ECM) protein expressed in normal epithelia, is a kind of fibulin which is associated with basement membranes (BM) and elastic ECM fibers. The role of fibulin-2 has been recognized as an oncogene. The upregulation of fibulin-2 correlates with cancer development and progression. Furthermore, the upregulation of fibulin has been detected in ovarian cancer and stomach adenocarcinoma. However, the downregulation of fibulin has been detected in different intestinal ...[more]

PMID: 31915327

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Project description:Colorectal carcinoma (CRC) is characterized by unlimited proliferation and suppression of apoptosis, selective advantages for tumor survival, and chemoresistance. Lipopolysaccharide (LPS) signaling is involved in both epithelial homeostasis and tumorigenesis, but the relative roles had by LPS receptor subunits CD14 and Toll-like receptor 4 (TLR4) are poorly understood. Our study showed that normal human colonocytes were CD14(+)TLR4(-), whereas cancerous tissues were CD14(+)TLR4(+), by immunofluorescent staining. Using a chemical-induced CRC model, increased epithelial apoptosis and decreased tumor multiplicity and sizes were observed in TLR4-mutant mice compared with wild-type (WT) mice with CD14(+)TLR4(+) colonocytes. WT mice intracolonically administered a TLR4 antagonist displayed tumor reduction associated with enhanced apoptosis in cancerous tissues. Mucosa-associated LPS content was elevated in response to CRC induction. Epithelial apoptosis induced by LPS hypersensitivity in TLR4-mutant mice was prevented by intracolonic administration of neutralizing anti-CD14. Moreover, LPS-induced apoptosis was observed in primary colonic organoid cultures derived from TLR4 mutant but not WT murine crypts. Gene silencing of TLR4 increased cell apoptosis in WT organoids, whereas knockdown of CD14 ablated cell death in TLR4-mutant organoids. In vitro studies showed that LPS challenge caused apoptosis in Caco-2 cells (CD14(+)TLR4(-)) in a CD14-, phosphatidylcholine-specific phospholipase C-, sphingomyelinase-, and protein kinase C-ζ-dependent manner. Conversely, expression of functional but not mutant TLR4 (Asp299Gly, Thr399Ile, and Pro714His) rescued cells from LPS/CD14-induced apoptosis. In summary, CD14-mediated lipid signaling induced epithelial apoptosis, whereas TLR4 antagonistically promoted cell survival and cancer development. Our findings indicate that dysfunction in the CD14/TLR4 antagonism may contribute to normal epithelial transition to carcinogenesis, and provide novel strategies for intervention against colorectal cancer.

Dataset Information

Roles of Fibulin-2 in Carcinogenesis.

Publications

Roles of Fibulin-2 in Carcinogenesis.

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