title: A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma.
abstract: HDGF is overexpressed in gliomas as compared to normal brain. We therefore analyzed the molecular mechanisms of HDGF action in gliomas. HDGF was downregulated in normal brain tissue as compared to glioma specimens at both the mRNA and the protein levels. In glioma samples, increased HDGF expression was associated with disease progression. Knocking down HDGF expression not only significantly decreased cellular proliferation, migration, invasion, and tumorigenesis, but also markedly enhanced TMZ-induced cytotoxicity and apoptosis in glioma cells. Mechanistic analyses revealed that CCND1, c-myc, and TGF-β were downregulated after stable HDGF knockdown in the U251 and U87 glioma cells. HDGF knockdown restored E-cadherin expression and suppressed mesenchymal cell markers such as vimentin, β-catenin, and N-cadherin. The expression of cleaved caspase-3 increased, while Bcl-2 decreased in each cell line following treatment with shHDGF and TMZ, as compared to TMZ alone. Furthermore, RNAi-based knockdown study revealed that HDGF is probably involved in the activation of both the PI3K/Akt and the TGF-β signaling pathways. Together, our data suggested that HDGF regulates glioma cell growth, apoptosis and epithelial-mesenchymal transition (EMT) probably through the Akt and the TGF-β signaling pathways. These results provide evidence that targeting HDGF or its downstream targets may lead to novel therapies for gliomas.
authors.affiliation: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Song
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hu
authors.forename: Hao
authors.initials: H
authors.lastname: Long
authors.forename: Yuping
authors.initials: Y
authors.lastname: Peng
authors.forename: Xi'an
authors.initials: X
authors.lastname: Zhang
authors.forename: Tianshi
authors.initials: T
authors.lastname: Que
authors.forename: Shihao
authors.initials: S
authors.lastname: Zheng
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Liu
authors.initials: L
authors.lastname: Yi
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Weiyi
authors.initials: W
authors.lastname: Fang
authors.forename: Songtao
authors.initials: S
authors.lastname: Qi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D015820:Cadherins / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002648:Child; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D000077204:Temozolomide; D016212:Transforming Growth Factor beta / Q000378:metabolism; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015820:Cadherins; D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; C051610:hepatoma-derived growth factor; D003606:Dacarbazine; D051057:Proto-Oncogene Proteins c-akt; D000077204:Temozolomide