BMP9 Promotes the Proliferation and Migration of Bladder Cancer Cells through Up-Regulating lncRNA UCA1

Gou, Liyao; Liu, Mengyao; Xia, Jing; Wan, Qun; Jiang, Yi; Sun, Shilei; Tang, Min; Zhou, Lan; He, Tong‐Chuan; Zhang, Yan

doi:10.3390/ijms19041116

Cited by 29 publications

(18 citation statements)

References 34 publications

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“…BMP9 is one of the most potent osteogenic BMPs both in vitro and in vivo [21,22,25], playing a role in several diseases [29,35,69,81,82,83]. Signaling by BMP9 is a synergistic factor regulating the proliferation and migration of specific cell types and stem cell differentiation through extensive crosstalk with several signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

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30Germ cell 1 spermatogonial (GC-1spg) cells are multipotent progenitor cells. We 31 previously confirmed that bone morphogenetic protein (BMP) 9 is among the most 32 osteogenic BMPs. However, whether GC-1spg cells are driven toward osteogenic 33 differentiation under proper stimuli is uncertain. Additionally, the molecular 34 mechanism of BMP9 remains unclear. In the present study, we aimed to determine 35 whether BMP9 can induce osteogenic differentiation of GC-1spg cells. Recombinant 36 adenoviruses were generated by the AdEasy system to regulate the BMP9 expression in 37 GC-1spg cells. We identified osteogenic markers by real-time PCR and staining 38 techniques in vitro. Ectopic ossification assays and histological analysis were also 39 performed to verify the in vivo activity of BMP9. Finally, potential signaling pathways 40 of BMP9 were assessed by transcriptome sequencing and KEGG enrichment analysis. 41Using recombinant adenoviruses, we demonstrate that BMP9 upregulates osteogenic 42 markers including Runx2, osteocalcin, osteopontin, and Sox9. BMP9 also activates 43 alkaline phosphatase activity and calcium deposition in GC-1spg cells. In vivo results 44show that BMP9 overexpression in GC-1spg cells promotes ectopic bone formation and 45 chondrogenesis. In addition, RNA-sequencing and KEGG pathway analysis 3 46 demonstrate that several signaling pathways are involved in BMP9-mediated 47 osteogenesis. GC-1spg cells not only maintain spermatogenesis but also retain the 48 ability to form bone tissue. Therefore, BMP9 activity in GC-1spg cells may help 49 identify signaling pathways implicated in bone formation and could be of use in 50 regenerative medicine. 51 Keywords: Bone morphogenetic protein 9, RNA-seq, KEGG pathway analysis, 52 recombinant adenovirus, chondrogenesis 53 Introduction 54 Germ cell 1 spermatogonial (GC-1spg) cells are mouse spermatogonia that are 55 immortalized by the SV40 large T antigen [1]. These cells can differentiate into diverse cell 56 types or undergo self-renewal, depending on different factors [2,3,4]. GC-1spg cells are 57 largely involved in spermatogenesis and have mesenchymal stem cell (MSC) differentiation 58 potential [5,6,7,8]. In other words, GC-1spg cells can differentiate into different cell types, 59including those of the osteogenic, chondrogenic, or adipogenic lineages [9,10,11,12]. 60However, several molecular events [13,14] and factors are involved in osteogenic 61 differentiation of MSCs. Importantly, bone morphogenetic proteins (BMPs) are essential for 62 this process [15,16,17]. 63 BMPs, members of the TGF-β superfamily, are required for bone formation, stem cell 64 differentiation, and male reproduction [15,16,18,19,20]. Thus far, more than 15 different 65 BMPs have been identified. Our previous work showed that BMP9 is the most osteogenic 66 BMP [21,22,23,24]. BMP9, also known as growth differentiation factor 2 (GDF-2)[25], was 67 originally isolated from the fetal mouse liver [25,26]. Bone formation involves BMP9 acting 68 through the Notch signaling ...

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Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

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“…BMP9 is overexpressed in bladder cancer and stimulates proliferation and migration of cancer cells by increasing the expression of lncRNA UCA1, which in turn leads to activation of AKT. BMP9 also stimulates the growth of bladder cancer tumors in vivo [224]. Another member of bone morphogenetic proteins (BMPs), the growth differentiation factor-9 (GDF-9), was suggested as a possible tumor suppressor in bladder cancer.…”

Section: Bladder Cancermentioning

confidence: 99%

TGF-β and microRNA Interplay in Genitourinary Cancers

Bogusławska¹,

Kryst

Poletajew

et al. 2019

Cells

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Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-β (transforming growth factor beta). TGF-β is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-β actions in cancer is hindered by the “TGF-β paradox” in which early stages of cancerogenic process are suppressed by TGF-β while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-β actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-β signaling in GCs. Importantly, TGF-β signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-β signaling pathway offers new potential treatment options for GC patients.

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“…Numerous studies have linked members of the BMP family, BMP antagonists, and BMP receptors to cancer (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). However, available data on involvement of BMP family members in cancerogenesis are conflicting.…”

Section: Discussionmentioning

confidence: 99%

“…However, expression of BMP-9 in bladder cancer tissue has recently been established. Given that the up regulation of BMP-9 promotes proliferation and migration of bladder cancer cells, it could be used as a novel marker of tumor aggressiveness (13).…”

Section: Discussionmentioning

confidence: 99%

“…BMPs have a critical function during normal mammalian development and cellular differentiation (8)(9)(10). Recent studies have also shown that they may play an important role in the regulation of malignant cells, including prostate (11) and bladder cancer (12,13). We have investigated BMP-6 and -7 in human clear cell renal carcinoma and we have found a significantly higher BMP-6 mRNA expression in malignant than in healthy tissue.…”

Section: Introductionmentioning

confidence: 90%

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Bone morphogenic proteins‑2, ‑4, ‑6 and 7 in non‑muscle invasive bladder cancer

et al. 2019

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Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) family and may play an important role in the regulation of malignant cells in bladder cancer. The aim of the present study was to investigate BMP expression in non-muscle invasive bladder cancer. Tumor tissue samples from 71 patients treated with transurethral resection and 10 samples of normal bladder tissue were stained using immunohistochemistry for BMP-2, -4, -6 and -7. The levels of BMP were correlated with the number and size of tumors in the bladder, the pathohistological findings as well as with tumor recurrence and progression. The results of the present study demonstrated that BMP-2 and -7 are highly expressed in normal bladder tissue, but significantly downregulated in cancer samples. This reduction correlates with a faster rate of tumor recurrence as well as with an increase in the number of recurrent tumors. There was no evident interrelation between BMP-2 and -7 reduction and changes in tumor grade and stage. In conclusion, BMP-2 and -7 are potential prognostic factors for tumor recurrence and further studies on BMP and bladder cancer are needed to confirm these results.

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BMP9 Promotes the Proliferation and Migration of Bladder Cancer Cells through Up-Regulating lncRNA UCA1

Cited by 29 publications

References 34 publications

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

TGF-β and microRNA Interplay in Genitourinary Cancers

Bone morphogenic proteins‑2, ‑4, ‑6 and 7 in non‑muscle invasive bladder cancer

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