Collagen Type VI Alpha 3 Chain Promotes Epithelial-Mesenchymal Transition in Bladder Cancer Cells via Transforming Growth Factor β (TGF-β)/Smad Pathway

Huang, Yan; Li, Gang; Wang, Kai; Mu, Zhongyi; Xie, Qingpeng; Qu, Hongchen; Lv, Hang

doi:10.12659/msm.909811

Cited by 31 publications

(26 citation statements)

References 50 publications

(42 reference statements)

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“…Huang et al showed that expression of COL6A3 is increased in bladder tumors, stimulates proliferation and angiopoiesis as well as epithelial-mesenchymal transition, with possible involvement of TGF-β. COL6A3 silencing resulted in reduced expression of TGF-β as well as phosphorylation of SMAD2 and SMAD3 [211]. Trim59, the expression of which is upregulated in bladder tumors, promotes proliferation, EMT, migration, and invasion of bladder cancer cells.…”

Section: Bladder Cancermentioning

confidence: 97%

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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Section: Bladder Cancermentioning

confidence: 97%

TGF-β and microRNA Interplay in Genitourinary Cancers

Bogusławska¹,

Kryst

Poletajew

et al. 2019

Cells

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“…In addition, COL6A3 may be involved during the EMT process induced by TGF-β/Smad. COL6A3 silencing inhibits cell proliferation and angiopoiesis [ 65 ], which is consistent with COL6A3 having a lower mutation rate in SCE_H and SCE_M, and a higher mutation rate in SCE_L. Additionally, activation of the hypoxic pathway helps cancer cells to be more adaptable to the hypoxic environment.…”

Section: Discussionmentioning

confidence: 57%

Development and validation of a novel stem cell subtype for bladder cancer based on stem genomic profiling

Tang

Liu

et al. 2020

Stem Cell Res Ther

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Background Bladder cancer (BLCA) is the fifth most common type of cancer worldwide, with high recurrence and progression rates. Although considerable progress has been made in the treatment of BLCA through accurate typing of molecular characteristics, little is known regarding the various genetic and epigenetic changes that have evolved in stem and progenitor cells. To address this issue, we have developed a novel stem cell typing method. Methods Based on six published genomic datasets, we used 26 stem cell gene sets to classify each dataset. Unsupervised and supervised machine learning methods were used to perform the classification. Results We classified BLCA into three subtypes—high stem cell enrichment (SCE_H), medium stem cell enrichment (SCE_M), and low stem cell enrichment (SCE_L)—based on multiple cross-platform datasets. The stability and reliability of the classification were verified. Compared with the other subtypes, SCE_H had the highest degree of cancer stem cell concentration, highest level of immune cell infiltration, and highest sensitivity not only to predicted anti-PD-1 immunosuppressive therapy but also to conventional chemotherapeutic agents such as cisplatin, sunitinib, and vinblastine; however, this group had the worst prognosis. Comparison of gene set enrichment analysis results for pathway enrichment of various subtypes reveals that the SCE_H subtype activates the important pathways regulating cancer occurrence, development, and even poor prognosis, including epithelial-mesenchymal transition, hypoxia, angiogenesis, KRAS signal upregulation, interleukin 6-mediated JAK-STAT signaling pathway, and inflammatory response. Two identified pairs of transcription factors, GRHL2 and GATA6 and IRF5 and GATA3, possibly have opposite regulatory effects on SCE_H and SCE_L, respectively. Conclusions The identification of BLCA subtypes based on cancer stem cell gene sets revealed the complex mechanism of carcinogenesis of BLCA and provides a new direction for the diagnosis and treatment of BLCA.

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“…TGF-β activates SMAD signaling and induces EMT in CRC cells. TGF-β, a multifunctional cytokine, can induce EMT in tumor cells via both SMAD-dependent and SMAD-independent activation of EMT-related transcription factors (21,22). Firstly, it was confirmed that 10 ng/ml TGF-β could activate classic SMAD signaling in CRC cells.…”

Section: Adspred2 Inhibits the Emt Of Crc Cells In Vitromentioning

confidence: 88%

“…EMT, which plays crucial roles in both embryonic development and tumor metastasis, is characterized by the loss of epithelial markers and acquisition of mesenchymal markers (31)(32)(33). TGF-β, a pleiotropic cytokine, is a pivotal molecule in the EMT processing of tumor cells and can activate EMT-related transcription factors in both SMAD-dependent and SMAD-independent manners (21,22,34). It was confirmed that 10 ng/ml TGF-β could activate SMAD signaling and increase cellular migration in CRC cells by promoting reorganization of the actin cytoskeleton and upregulating vimentin expression.…”

Section: Discussionmentioning

confidence: 99%

Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling

Wang¹,

Liu²,

Kong³

et al. 2020

Oncol Rep

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Downregulation of the sprouty-related EVH1 domain protein 2 (Spred2) is closely associated with highly metastatic phenotypes in various tumors. However, the roles of Spred2 in the development and progression of colorectal cancer (CRC) are still largely unexplored. As anticipated, Spred2 expression was significantly downregulated in clinical tumor tissues. To restore Spred2 levels, Ad.Spred2, an adenoviral vector expressing Spred2, was transduced into CRC cells. It was revealed that Ad.Spred2 inhibited the proliferation and decreased the survival and migration of SW480 cells. Epithelial-mesenchymal transition (EMT) is an essential event during tumor metastasis to distant sites. It was revealed that Ad.Spred2 markedly inhibited EMT by promoting F-actin reorganization, upregulating E-cadherin levels and reducing vimentin protein expression. Notably, extracellular-regulated kinase (ERK) signaling inhibition by PD98059 induced similar effects on EMT in CRC cells, indicating that Ad.Spred2 regulated EMT in CRC cells in an ERK-dependent manner. Transforming growth factor β (TGF-β), a well-known inducer of EMT, increased E-cadherin expression, decreased vimentin expression and promoted migration in CRC cells. However, neither Ad.Spred2 nor PD98059 had an obvious effect on the expression of SMAD2/3 or SMAD4 in SW480 cells, indicating that Ad.Spred2 inhibited EMT in a SMAD-independent manner. Notably, Ad.Spred2 transduction downregulated SAMD2/3 and SMAD4 levels in HCT116 cells in an ERK-independent manner. It was speculated that Ad.Spred2 inhibited the EMT of HCT116 cells by both blocking ERK signaling and reducing SMAD signaling. It was concluded that Spred2 inhibited EMT in CRC cells by interfering with ERK signaling, with or without reduced SMAD signaling. Therefore, the introduction of the clinical application of Spred2 has great potential for development as a gene therapy approach for CRC.

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Collagen Type VI Alpha 3 Chain Promotes Epithelial-Mesenchymal Transition in Bladder Cancer Cells via Transforming Growth Factor β (TGF-β)/Smad Pathway

Cited by 31 publications

References 50 publications

TGF-β and microRNA Interplay in Genitourinary Cancers

TGF-β and microRNA Interplay in Genitourinary Cancers

Development and validation of a novel stem cell subtype for bladder cancer based on stem genomic profiling

Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling

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