Dataset Information

Cry 1 Regulates the Clock Gene Network and Promotes Proliferation and Migration Via the Akt/P53/P21 Pathway in Human Osteosarcoma Cells.

ABSTRACT: The many circadian clock genes buildup a network structure that controls physiological processes such as sleep cycle, metabolism and hormone secretion. A close relationship exists between circadian rhythm and cancers because cell cycle is affected by clock controlled genes (CCGs), including Cyclin D1, Cyclin A, Cyclin E and P21. The abnormal expression of the core circadian clock gene Cryptochrome 1 (Cry1) was found in many types of cancers. However, it is still unclear the exact mechanism of Cry1 dysregulation influences carcinogenesis and progression of cancers. In this study, we investigated the role of Cry1 in regulating proliferation and migration of Hos and U2os human osteosarcoma cells by silencing Cry1 using short hairpin RNA interference. Our data from in vitro and in vivo experiments confirmed that Cry1 knockdown enhanced proliferation and migration of osteosarcoma cells. Then, Cry2, Per1, Per2, Per3, Bmal1 and Clock were found up regulated, while Dec1, Dec2, CK1? and Npas2 were downregulated at mRNA level. Besides, Akt/P53/P21 signaling was activated after Cry1 silencing and Akt was negatively phosphorylated along with Cry1 expression, while enhanced progression of osteosarcoma cells by Cry1 knockdown was reversed when Akt inhibitor treated. Furthermore, the rescue experiment verified the Akt/P53/P21 was downstream genes of Cry1 to control osteosarcoma progression. Taken together, these findings provide a new insight into how Cry1 regulates clock gene network and promotes proliferation and migration in a Akt dependent manner in human osteosarcoma cells.

SUBMITTER: Zhou L

PROVIDER: S-EPMC6036881 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Cry 1 Regulates the Clock Gene Network and Promotes Proliferation and Migration Via the Akt/P53/P21 Pathway in Human Osteosarcoma Cells.

Zhou Lei L Yu Yueming Y Sun Shiwei S Zhang Tieqi T Wang Minghai M

Journal of Cancer 20180614 14

The many circadian clock genes buildup a network structure that controls physiological processes such as sleep cycle, metabolism and hormone secretion. A close relationship exists between circadian rhythm and cancers because cell cycle is affected by clock controlled genes (CCGs), including Cyclin D1, Cyclin A, Cyclin E and P21. The abnormal expression of the core circadian clock gene Cryptochrome 1 (Cry1) was found in many types of cancers. However, it is still unclear the exact mechanism of Cr ...[more]

PMID: 30026846

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Project description:BackgroundOsteosarcoma is the most common primary bone cancer in children and young adults. It is highly aggressive and patients that present with metastasis have a poor prognosis. Angiopoietin-like 4 (ANGPTL4) drives the progression and metastasis of many solid tumours, but has not been described in osteosarcoma tissue. ANGPTL4 also enhances osteoclast activity, which is required for osteosarcoma growth in bone. We therefore investigated the expression and function of ANGPTL4 in human osteosarcoma tissue and cell lines.MethodsExpression of ANGPTL4 in osteosarcoma tissue microarrays was determined by immunohistochemistry. Hypoxic secretion of ANGPTL4 was tested by ELISA and Western blot. Regulation of ANGPTL4 by hypoxia-inducible factor (HIF) was investigated using isoform specific HIF siRNA (HIF-1α, HIF-2α). Effects of ANGPTL4 on cell proliferation, migration (scratch wound assay), colony formation and osteoblastogenesis were assessed using exogenous ANGPTL4 or cells stably transfected with ANGPTL4. Osteoclastogenic differentiation of CD14+ monocytes was assessed by staining for tartrate-resistant acid phosphatase (TRAP), bone resorption was assessed by lacunar resorption of dentine.ResultsANGPTL4 was immunohistochemically detectable in 76/109 cases. ANGPTL4 was induced by hypoxia in 6 osteosarcoma cell lines, under the control of the HIF-1α transcription factor. MG-63 cells transfected with an ANGPTL4 over-expression plasmid exhibited increased proliferation and migration capacity and promoted osteoclastogenesis and osteoclast-mediated bone resorption. Individually the full-length form of ANGPTL4 could increase MG-63 cell proliferation, whereas N-terminal ANGPTL4 mediated the other pro-tumourigenic phenotypes.ConclusionsThis study describes a role(s) for ANGPTL4 in osteosarcoma and identifies ANGPTL4 as a treatment target that could potentially reduce tumour progression, inhibit angiogenesis, reduce bone destruction and prevent metastatic events.

Dataset Information

Cry 1 Regulates the Clock Gene Network and Promotes Proliferation and Migration Via the Akt/P53/P21 Pathway in Human Osteosarcoma Cells.

Publications

Cry 1 Regulates the Clock Gene Network and Promotes Proliferation and Migration Via the Akt/P53/P21 Pathway in Human Osteosarcoma Cells.

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