title: Targeting Transforming Growth Factor-Beta1 (TGF-β1) Inhibits Tumorigenesis of Anaplastic Thyroid Carcinoma Cells Through ERK1/2-NFκkB-PUMA Signaling.
abstract: BACKGROUND The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in promoting tumor growth. TGF-β1was found to be overexpressed in anaplastic thyroid cancer (ATC). We therefore tested our hypothesis that targeting TGF-β1 inhibits tumorigenesis of ATC cells. MATERIAL AND METHODS Effects of TGF-β1 stimulation or TGF-β1 inhibition by small interfering RNA (TGF-β1siRNA) on proliferation, colony formation, and apoptosis in 8505C cells in vitro was detected using siRNAs and inhibitors to examine the TGF-β1 signaling pathway. A subcutaneously implanted tumor model of 8505C cells in nude mice was used to assess the effects of TGF-β1 inhibition on tumorigenesis development. RESULTS TGF-β1siRNAs decreased proliferation and colony formation, and increased apoptosis in 8505C cells in vitro and inhibited tumor growth in vivo. TGF-β1siRNA inhibited phosphorylation ERK1/2 (pERK1/2) and increased p65-dependant PUMA mRNA and protein expression. Knockdown of p65 or PUMA by siRNA reduced TGF-β1siRNA-induced apoptosis, as well as caspase-3 and PARP activation. Upregulation of p65 or PUMA expression by TGF-β1siRNA requires pERK1/2 inhibition. TGF-β1 shRNA inhibited tumor growth in vivo. CONCLUSIONS Therapies targeting the TGF-β1 pathway may be more effective to prevent primary tumor formation. The ability of this therapy to decrease tumorigenesis may be related to ERK1/2/NF-κB/PUMA signaling.
authors.affiliation: Department of Oncology, People's Hospital of Rizhao, Rizhao, Shandong, China (mainland).
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Department of Oncology, People's Hospital of Rizhao, Rizhao, Shandong, China (mainland).
authors.forename: Shan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland).
authors.forename: Anbing
authors.initials: A
authors.lastname: Dong
authors.affiliation: Department of Internal Medicine, People's Hospital of Zhangqiu, Jinan, Shandong, China (mainland).
authors.forename: Xiufang
authors.initials: X
authors.lastname: Mi
authors.affiliation: Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland).
authors.forename: Fengyun
authors.initials: F
authors.lastname: Hao
authors.affiliation: Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland).
authors.forename: Kejun
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D053148:Caspase 3