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Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad.

ABSTRACT: Interstitial flow in and around tumor tissue affects the mechanical microenvironment to modulate tumor cell growth and metastasis. We investigated the roles of flow-induced shear stress in modulating cell cycle distribution in four tumor cell lines and the underlying mechanisms. In all four cell lines, incubation under static conditions for 24 or 48 h led to G(0)/G(1) arrest; in contrast, shear stress (12 dynes/cm(2)) induced G(2)/M arrest. The molecular basis of the shear effect was analyzed, and the presentation on molecular mechanism is focused on human MG63 osteosarcoma cells. Shear stress induced increased expressions of cyclin B1 and p21(CIP1) and decreased expressions of cyclins A, D1, and E, cyclin-dependent protein kinases (Cdk)-1, -2, -4, and -6, and p27(KIP1) as well as a decrease in Cdk1 activity. Using specific antibodies and small interfering RNA, we found that the shear-induced G(2)/M arrest and corresponding changes in G(2)/M regulatory protein expression and activity were mediated by alpha(v)beta(3) and beta(1) integrins through bone morphogenetic protein receptor type IA-specific Smad1 and Smad5. Shear stress also down-regulated runt-related transcription factor 2 (Runx2) binding activity and osteocalcin and alkaline phosphatase expressions in MG63 cells; these responses were mediated by alpha(v)beta(3) and beta(1) integrins through Smad5. Our findings provide insights into the mechanism by which shear stress induces G(2)/M arrest in tumor cells and inhibits cell differentiation and demonstrate the importance of mechanical microenvironment in modulating molecular signaling, gene expression, cell cycle, and functions in tumor cells.

SUBMITTER: Chang SF

PROVIDER: S-EPMC2268796 | biostudies-other | 2008 Mar

REPOSITORIES: biostudies-other

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Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad.

Chang Shun-Fu SF Chang Cheng Allen CA Lee Ding-Yu DY Lee Pei-Ling PL Yeh Yu-Ming YM Yeh Chiuan-Ren CR Cheng Cheng-Kung CK Chien Shu S Chiu Jeng-Jiann JJ

Proceedings of the National Academy of Sciences of the United States of America 20080229 10

Interstitial flow in and around tumor tissue affects the mechanical microenvironment to modulate tumor cell growth and metastasis. We investigated the roles of flow-induced shear stress in modulating cell cycle distribution in four tumor cell lines and the underlying mechanisms. In all four cell lines, incubation under static conditions for 24 or 48 h led to G(0)/G(1) arrest; in contrast, shear stress (12 dynes/cm(2)) induced G(2)/M arrest. The molecular basis of the shear effect was analyzed, a ...[more]

PMID: 18310319

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Project description:Endometriosis is associated with benign but adversely developed cysts in the extrauterine environment. The oxidative imbalanced environment induces DNA damage and affects cell cycle progression of endometrial stromal cells (ESCs) and endometrial epithelial cells, but how endometriotic cells maintain proliferation in the presence of oxidative stress is not clear. Growing evidence has indicated that the ectopic hypoxic microenvironment and oxidative stress can stimulate the growth of endometriotic cells, which is mainly due to the increase of HIF-1?. We found that the master hypoxia-associated miRNA miR-210-3p was increased in stromal and glandular cells of ectopic lesions compared with that of eutopic and normal endometria and was consistent with the expression of HIF-1? and the local oxidative stress-induced DNA damage predictor 8-OHdG. Moreover, miR-210-3p was upregulated in ESCs and Ishikawa cells under hypoxic conditions but not in normoxic culture. Knockdown of miR-210-3p induced a G2/M arrest of ESCs and Ishikawa cells under hypoxia, while no effect was found under normoxia. BARD1 was identified as a target of miR-210-3p. BARD1 expression was decreased in endometriotic tissues compared with eutopic and normal endometria and negatively correlated with the expression of miR-210-3p. Multivariate regression analysis showed that BARD1 downregulation could serve as an indicator for endometriotic severity. Our results suggest that miR-210-3p attenuates the G2/M cell cycle checkpoint by inactivating BRCA1 complex function in response to DNA damage under hypoxia via targeting the 3' untranslated region of BARD1 mRNA. Endometriotic mouse model experiments showed that intraperitoneal injection of the miR-210-3p inhibitor or vitamin C suppressed the growth of endometriotic lesions. Together, our results demonstrate that endometriotic cells inhibit BARD1/BRCA1 function by upregulating miR-210-3p, which might be the underlying mechanism for endometriotic cell maintenance of growth in oxidative stress. Furthermore, inhibition of miR-210-3p and administration of vitamin C are promising approaches for the treatment of endometriosis.

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Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad.

Publications

Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad.

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