title: Transcriptional factor specificity protein 1 (SP1) promotes the proliferation of glioma cells by up-regulating midkine (MDK).
abstract: Midkine (MDK) expression is associated with the proliferation of many cancers, including glioma. However, the upstream signaling that leads to MDK accumulation remains elusive. This study investigates the molecular mechanism that induces MDK overexpression in human glioma. The Repository for Molecular Brain Neoplasia Data was analyzed to identify potential MDK regulators. Expression of MDK and specificity protein 1 (SP1) was compared in glioma specimens. Chromatin immunoprecipitation assay was used to confirm the transcriptional regulation. MDK-force-expressed, SP1-silenced glioma cells were used to test rescue effects in vitro and in vivo. MDK and SP1 expression in gliomas was significantly higher than in adjacent tissues and was positively correlated in glioma clinical samples and cell lines. The promoter of the human MDK gene has a putative SP1 binding site. SP1 binds to the promoter of the MDK gene and directly regulates MDK expression. MDK or SP1 gene silencing inhibited the proliferation of glioma cells and reduced the tumor volume in nude mice. Overexpression of MDK in SP1-silenced cells could partially rescue the SP1 inhibition effects in vivo and in vitro. SP1 directly up-regulated the expression of MDK, and the SP1-MDK axis cooperated in glioma tumorigenesis.
authors.affiliation: Forevergen Biosciences Center, R&D Unit 602, Guangzhou 510000, China Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Lixuan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Huang Pu Division, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Neurology and Northwestern Brain Tumor Institute, Center of Genetic Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611.
authors.forename: Shiyuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Forevergen Biosciences Center, R&D Unit 602, Guangzhou 510000, China lbq@forevergen.cn zhangnu1008@163.com.
authors.forename: Bingquan
authors.initials: B
authors.lastname: Lai
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China lbq@forevergen.cn zhangnu1008@163.com.
authors.forename: Nu
authors.initials: N
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000078792:Midkine; D009414:Nerve Growth Factors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C066254:MDK protein, human; D009414:Nerve Growth Factors; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D000078792:Midkine