title: Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex.
abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder featured with multi-organ benign tumours. Disruption of TSC1/TSC2 complex suppression on mammalian/mechanistic target of rapamycin (mTOR) signalling causes TSC. Hyperactive mTOR-mediated negative feedback regulation of AKT partially contributes to the benign nature of TSC-associated tumours. In this study, we demonstrated that osteopontin (OPN) was dramatically reduced by loss of TSC1/TSC2 complex in Tsc2-null mouse embryonic fibroblasts (MEFs), rat uterine leiomyoma-derived Tsc2-deficient cells, genetically modified mouse TSC models, and clinical samples. TSC1/TSC2 complex upregulation of OPN expression is mediated by transcription factor SOX9 in an mTOR-independent manner. Moreover, ablation of OPN by deficient TSC1/TSC2 complex contributed to inactivation of AKT in TSC cells. Lastly, the abundance of OPN dictated the potency of cell proliferation and tumour development. Therefore, loss of TSC1/TSC2 complex led to mTOR-independent inhibition of AKT at least partially through downregulation of the SOX9-OPN signalling cascade. We suggest that the decreased SOX9-OPN-AKT signalling pathway safeguard against the development of malignant tumours in TSC patients.
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China.|Department of Nephrology, The Third Affiliated Hospital, Anhui Medical University, Hefei, People's Republic of China.
authors.forename: Keguo
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China.|Department of Respiratory Medicine, The First Affiliated Hospital, Anhui Medical University, Hefei, People's Republic of China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China.
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Ni
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China and.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China and.
authors.forename: Chunjia
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China and.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China and.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China.|Institute of Dermatology, Anhui Medical University, Hefei, People's Republic of China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zha
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000235:genetics*; D053495:Osteopontin / Q000235:genetics*; D051381:Rats; D055758:SOX9 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D053495:Osteopontin; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases