MicroRNA-203 inhibits long noncoding RNA hotair and regulates tumorigenesis through epithelial-to-mesenchymal transition pathway in renal cell carcinoma

Pritha Dasgupta, Priyanka Kulkarni, Shahana Majid, Varahram Shahryari, Yutaka Hashimoto, Nadeem S. Bhat, Marisa Shiina, Guoren Deng, Sharanjot Saini, Z. Laura Tabatabai, Soichiro Yamamura, Yuichiro Tanaka, Rajvir Dahiya

Research output: Contribution to journalArticle

Abstract

This study aims to investigate the role of miR-203–HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration, and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly underexpressed, whereas HOTAIR was overexpressed in RCC cell lines and clinical specimens compared with normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathologic characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration, and invasion with an induction of apoptosis and cell-cycle arrest. However, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico, RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203–HOTAIR interaction resulted in the inhibition of epithelial-to-mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers), and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal marker), KLF4, and Nanog (stemness markers) was also observed. This is the first report demonstrating miR-203–mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis.

Original languageEnglish (US)
Pages (from-to)1061-1069
Number of pages9
JournalMolecular cancer therapeutics
Volume17
Issue number5
DOIs
StatePublished - May 2018
Externally publishedYes

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Long Noncoding RNA
Epithelial-Mesenchymal Transition
MicroRNAs
Renal Cell Carcinoma
Carcinogenesis
Cell Line
RNA
Neoplasm Metastasis
Vimentin
Cadherins
Cell Cycle Checkpoints
Tumor Suppressor Genes
Luciferases
Immunoprecipitation
Heterografts
Computer Simulation
Genes
Neoplasms
Binding Sites
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MicroRNA-203 inhibits long noncoding RNA hotair and regulates tumorigenesis through epithelial-to-mesenchymal transition pathway in renal cell carcinoma. / Dasgupta, Pritha; Kulkarni, Priyanka; Majid, Shahana; Shahryari, Varahram; Hashimoto, Yutaka; Bhat, Nadeem S.; Shiina, Marisa; Deng, Guoren; Saini, Sharanjot; Laura Tabatabai, Z.; Yamamura, Soichiro; Tanaka, Yuichiro; Dahiya, Rajvir.

In: Molecular cancer therapeutics, Vol. 17, No. 5, 05.2018, p. 1061-1069.

Research output: Contribution to journalArticle

Dasgupta, P, Kulkarni, P, Majid, S, Shahryari, V, Hashimoto, Y, Bhat, NS, Shiina, M, Deng, G, Saini, S, Laura Tabatabai, Z, Yamamura, S, Tanaka, Y & Dahiya, R 2018, 'MicroRNA-203 inhibits long noncoding RNA hotair and regulates tumorigenesis through epithelial-to-mesenchymal transition pathway in renal cell carcinoma', Molecular cancer therapeutics, vol. 17, no. 5, pp. 1061-1069. https://doi.org/10.1158/1535-7163.MCT-17-0925
Dasgupta, Pritha ; Kulkarni, Priyanka ; Majid, Shahana ; Shahryari, Varahram ; Hashimoto, Yutaka ; Bhat, Nadeem S. ; Shiina, Marisa ; Deng, Guoren ; Saini, Sharanjot ; Laura Tabatabai, Z. ; Yamamura, Soichiro ; Tanaka, Yuichiro ; Dahiya, Rajvir. / MicroRNA-203 inhibits long noncoding RNA hotair and regulates tumorigenesis through epithelial-to-mesenchymal transition pathway in renal cell carcinoma. In: Molecular cancer therapeutics. 2018 ; Vol. 17, No. 5. pp. 1061-1069.
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abstract = "This study aims to investigate the role of miR-203–HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration, and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly underexpressed, whereas HOTAIR was overexpressed in RCC cell lines and clinical specimens compared with normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathologic characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration, and invasion with an induction of apoptosis and cell-cycle arrest. However, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico, RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203–HOTAIR interaction resulted in the inhibition of epithelial-to-mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers), and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal marker), KLF4, and Nanog (stemness markers) was also observed. This is the first report demonstrating miR-203–mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis.",
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AU - Dasgupta, Pritha

AU - Kulkarni, Priyanka

AU - Majid, Shahana

AU - Shahryari, Varahram

AU - Hashimoto, Yutaka

AU - Bhat, Nadeem S.

AU - Shiina, Marisa

AU - Deng, Guoren

AU - Saini, Sharanjot

AU - Laura Tabatabai, Z.

AU - Yamamura, Soichiro

AU - Tanaka, Yuichiro

AU - Dahiya, Rajvir

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N2 - This study aims to investigate the role of miR-203–HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration, and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly underexpressed, whereas HOTAIR was overexpressed in RCC cell lines and clinical specimens compared with normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathologic characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration, and invasion with an induction of apoptosis and cell-cycle arrest. However, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico, RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203–HOTAIR interaction resulted in the inhibition of epithelial-to-mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers), and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal marker), KLF4, and Nanog (stemness markers) was also observed. This is the first report demonstrating miR-203–mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis.

AB - This study aims to investigate the role of miR-203–HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration, and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly underexpressed, whereas HOTAIR was overexpressed in RCC cell lines and clinical specimens compared with normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathologic characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration, and invasion with an induction of apoptosis and cell-cycle arrest. However, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico, RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203–HOTAIR interaction resulted in the inhibition of epithelial-to-mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers), and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal marker), KLF4, and Nanog (stemness markers) was also observed. This is the first report demonstrating miR-203–mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis.

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