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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.

Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex