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SMAD3/SP1 complex-mediated constitutive active loop between lncRNA PCAT7 and TGF-? signaling promotes prostate cancer bone metastasis.

ABSTRACT: Bone metastasis is associated with cancer-related death in patients with prostate cancer (PCa). Long noncoding RNAs (lncRNAs) play critical roles in tumor progression of PCa. Nevertheless, the biological function of lncRNAs in PCa bone metastasis remains unclear. PCAT7 was identified as a bone metastasis-related lncRNA via analyzing TCGA dataset. Meanwhile, PCAT7 was found to be elevated in primary PCa tissues with bone metastasis and associated with bone metastasis status and poor prognosis of patients with PCa. Functionally, our results reveal that PCAT7 overexpression promotes PCa bone metastasis in vivo, as well as migration, invasion, and EMT of PCa cells in vitro; on the contrary, PCAT7 knockdown has an inverse effect. Mechanistically, PCAT7 activates TGF-?/SMAD signaling by upregulating TGFBR1 expression via sponging miR-324-5p. In turn, TGF-? signaling forms a positive feedback loop with PCAT7 via SMAD3/SP1 complex-induced PCAT7 upregulation. Finally, the clinical positive correlation between PCAT7 and TGFBR1 and TGF-? signaling activity, and the negative association with miR-324-5p are further demonstrated in PCa tissues and clinical primary PCa cells. This study reveals a novel mechanism that is responsible for the constitutive activation of TGF-? signaling in PCa bone metastasis, implying that PCAT7 can act as a potential therapeutic target against bone metastasis of PCa via disrupting the constitutive active loop between PCAT7 and TGF-? signaling.

SUBMITTER: Lang C

PROVIDER: S-EPMC7138406 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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SMAD3/SP1 complex-mediated constitutive active loop between lncRNA PCAT7 and TGF-β signaling promotes prostate cancer bone metastasis.

Lang Chuandong C Dai Yuhu Y Wu Zhengquan Z Yang Qing Q He Shaofu S Zhang Xin X Guo Wei W Lai Yingrong Y Du Hong H Wang Hehe H Ren Dong D Peng Xinsheng X

Molecular oncology 20200208 4

Bone metastasis is associated with cancer-related death in patients with prostate cancer (PCa). Long noncoding RNAs (lncRNAs) play critical roles in tumor progression of PCa. Nevertheless, the biological function of lncRNAs in PCa bone metastasis remains unclear. PCAT7 was identified as a bone metastasis-related lncRNA via analyzing TCGA dataset. Meanwhile, PCAT7 was found to be elevated in primary PCa tissues with bone metastasis and associated with bone metastasis status and poor prognosis of ...[more]

PMID: 31925912

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Project description:Background: The reciprocal repressive loop between ZEB1 and miRNAs has been extensively reported to play an important role in tumor progression and metastasis of various human tumor types. The aim of this study was to elucidate the role and the underlying mechanism of the double-negative feedback loop between ZEB1and miR-33a-5p in bone metastasis of prostate cancer (PCa). Methods: miR-33a-5p expression was examined in 40 bone metastatic and 165 non-bone metastatic PCa tissues by real-time PCR. Statistical analysis was performed to evaluate the clinical correlation between miR-33a-5p expression and clinicopathological characteristics, and overall and bone metastasis-free survival in PCa patients. The biological roles of miR-33a-5p in bone metastasis of PCa were investigated both by EMT and the Transwell assay in vitro, and by a mouse model of left cardiac ventricle inoculation in vivo. siRNA library, real-time PCR and chromatin immunoprecipitation (ChIP) were used to identify the underlying mechanism responsible for the decreased expression of miR-33a-5p in PCa. Bioinformatics analysis, Western blotting and luciferase reporter analysis were employed to examine the relationship between miR-33a-5p and its potential targets. Clinical correlation of miR-33a-5p with its targets was examined in human PCa tissues and primary PCa cells. Results: miR-33a-5p expression was downregulated in PCa tissues with bone metastasis and bone-derived cells, and low expression of miR-33a-5p strongly and positively correlated with advanced clinicopathological characteristics, and shorter overall and bone metastasis-free survival in PCa patients. Upregulating miR-33a-5p inhibited, while silencing miR-33a-5p promoted EMT, invasion and migration of PCa cells. Importantly, upregulating miR-33a-5p significantly repressed bone metastasis of PC-3 cells in vivo. Our results further revealed that recurrent ZEB1 upregulation induced by copy number gains transcriptionally inhibited miR-33a-5p expression, contributing to the reduced expression of miR-33a-5p in bone metastatic PCa tissues. In turn, miR-33a-5p formed a double negative feedback loop with ZEB1 in target-independent manner, which was dependent on TGF-β signaling. Finally, the clinical negative correlations of miR-33a-5p with ZEB1 expression and TGF-β signaling activity were demonstrated in PCa tissues and primary PCa cells. Conclusion: Our findings elucidated that copy number gains of ZEB1-triggered a TGF-β signaling-dependent miR-33a-5p-mediated negative feedback loop was highly relevant to the bone metastasis of PCa.

Dataset Information

SMAD3/SP1 complex-mediated constitutive active loop between lncRNA PCAT7 and TGF-? signaling promotes prostate cancer bone metastasis.

Publications

SMAD3/SP1 complex-mediated constitutive active loop between lncRNA PCAT7 and TGF-β signaling promotes prostate cancer bone metastasis.

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