Role of Cathepsin K in Bone Invasion of Pituitary Adenomas: A Dual Mechanism Involving Cell Proliferation and Osteoclastogenesis
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PROVIDER: PRJNA1166200 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: This study aimed to investigate the regulation and underlying mechanism of Cathepsin K (CTSK) in bone-invasive pituitary adenomas (BIPAs). Experimental Design: A total of 1437 patients with pituitary adenomas were included and followed up. RNA sequencing, immunohistochemistry, and RT-PCR were used to analyze to detect CTSK expression. The effects of CTSK on cellular proliferation, bone matrix degradation, and osteoclast differentiation were determined by gain/loss of function experiments in vitro and in vivo. The exploration of signaling pathways was determined by molecular biology experiments. Results: Here, we reported a significant fraction (~10%) of pituitary adenoma patients developed bone invasion, which was correlated with tumor recurrence. Patients with BIPAs had shorter recurrence-free survival. CTSK expression was increased in BIPA patients and was strongly associated with a worse prognosis. Increased CTSK expression enhanced pituitary adenoma cell proliferation through the activation of the mammalian target of rapamycin (mTOR) signaling pathway and promoted bone invasion by increasing osteoclast differentiation both in vitro and in vivo. Treatment with the CTSK inhibitor odanacatib effectively inhibited pituitary adenoma cell proliferation and bone invasion in these models. Additionally, CTSK facilitated osteoclast differentiation by promoting RANKL expression in MC3T3-E1 cells via interaction with TLR4. Conclusion: CTSK has the potential to become a novel predictive biomarker and therapeutic target for BIPAs.
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Project description:Gonadotroph adenomas comprise 15–40 % of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we dem¬onstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrep¬resentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. Bioinfor¬matic analysis identified downstream targets of the transcrip¬tion factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similari¬ties between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95 % of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonado¬troph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma pri¬mary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use.
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Project description:Gonadotroph adenomas comprise 15M-bM-^@M-^S40 % of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we demM-BM-,onstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrepM-BM-,resentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. BioinforM-BM-,matic analysis identified downstream targets of the transcripM-BM-,tion factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similariM-BM-,ties between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95 % of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonadoM-BM-,troph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma priM-BM-,mary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use. We compared five control animals and 16 homozygous mutants (p27Kip1/Cdknb1)
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