An atypical system for studying epithelial-mesenchymal transition in hepatocellular carcinoma

Dhiviya  Vedagiri; Hiren Vasantrai  Lashkari; Abubakar Siddiq Mangani; Jerald Mahesh  Kumar; Jedy Jose; Avinash Raj  Thatipalli; Krishnan Harinivas  Harshan

doi:10.1038/srep26282

An atypical system for studying epithelial-mesenchymal transition in hepatocellular carcinoma

Dhiviya Vedagiri, Hiren Vasantrai Lashkari, Abubakar Siddiq Mangani, Jerald Mahesh Kumar, Jedy Jose, Avinash Raj Thatipalli, Krishnan Harinivas Harshan

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Abstract

Intrahepatic and extrahepatic metastases are frequently detected in hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is believed to drive metastasis. There are not many well-established model systems to study EMT in HCC. Here we identified an atypical EMT while characterizing a population of mesenchymal cells in Huh7.5 hepatoma cell cultures. Cells with distinct morphology appeared during geneticin treatment of Huh7.5 cultures. Molecular characterization of geneticin resistant Huh7.5M cells confirmed EMT. Huh7.5M cells expressed cancer stem cell markers. p38MAPK and ERK1/2 were substantially activated in Huh7.5M cells. Their Inhibition elevated E-Cadherin expression with concerted suppression of Vimentin and anchorage independent growth in Huh7.5M cells. TGFβ could not induce EMT in Huh7.5 cultures, but enriched mesenchymal populations, similar to geneticin. Huh7.5M cells formed more aggressive solid tumors, primarily comprising cells with epithelial morphology, in nude mice. Canonical EMT-TFs did not participate in this atypical EMT, indicating that the established canonical EMT-TFs do not drive every EMT and there is a dire need to identify additional factors. The system that we characterized is a unique model to study EMT, MET and biphasic TGFβ signaling in HCC and offers considerable potential to facilitate more insightful studies on deeper questions in tumor metastasis.

Original language	English
Article number	26282
Pages (from-to)	1-13
Number of pages	13
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep26282
Publication status	Published - 20 May 2016
Externally published	Yes

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Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Vedagiri, D., Lashkari, H. V., Mangani, A. S., Kumar, J. M., Jose, J., Thatipalli, A. R., & Harshan, K. H. (2016). An atypical system for studying epithelial-mesenchymal transition in hepatocellular carcinoma. Scientific Reports, 6, 1-13. [26282]. https://doi.org/10.1038/srep26282

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abstract = "Intrahepatic and extrahepatic metastases are frequently detected in hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is believed to drive metastasis. There are not many well-established model systems to study EMT in HCC. Here we identified an atypical EMT while characterizing a population of mesenchymal cells in Huh7.5 hepatoma cell cultures. Cells with distinct morphology appeared during geneticin treatment of Huh7.5 cultures. Molecular characterization of geneticin resistant Huh7.5M cells confirmed EMT. Huh7.5M cells expressed cancer stem cell markers. p38MAPK and ERK1/2 were substantially activated in Huh7.5M cells. Their Inhibition elevated E-Cadherin expression with concerted suppression of Vimentin and anchorage independent growth in Huh7.5M cells. TGFβ could not induce EMT in Huh7.5 cultures, but enriched mesenchymal populations, similar to geneticin. Huh7.5M cells formed more aggressive solid tumors, primarily comprising cells with epithelial morphology, in nude mice. Canonical EMT-TFs did not participate in this atypical EMT, indicating that the established canonical EMT-TFs do not drive every EMT and there is a dire need to identify additional factors. The system that we characterized is a unique model to study EMT, MET and biphasic TGFβ signaling in HCC and offers considerable potential to facilitate more insightful studies on deeper questions in tumor metastasis.",

author = "Dhiviya Vedagiri and Lashkari, {Hiren Vasantrai} and Mangani, {Abubakar Siddiq} and Kumar, {Jerald Mahesh} and Jedy Jose and Thatipalli, {Avinash Raj} and Harshan, {Krishnan Harinivas}",

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An atypical system for studying epithelial-mesenchymal transition in hepatocellular carcinoma. / Vedagiri, Dhiviya ; Lashkari, Hiren Vasantrai ; Mangani, Abubakar Siddiq; Kumar, Jerald Mahesh ; Jose, Jedy; Thatipalli, Avinash Raj ; Harshan, Krishnan Harinivas .

In: Scientific Reports, Vol. 6, 26282, 20.05.2016, p. 1-13.

Research output: Contribution to journal › Article

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AU - Vedagiri, Dhiviya

AU - Lashkari, Hiren Vasantrai

AU - Mangani, Abubakar Siddiq

AU - Kumar, Jerald Mahesh

AU - Jose, Jedy

AU - Thatipalli, Avinash Raj

AU - Harshan, Krishnan Harinivas

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PY - 2016/5/20

Y1 - 2016/5/20

N2 - Intrahepatic and extrahepatic metastases are frequently detected in hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is believed to drive metastasis. There are not many well-established model systems to study EMT in HCC. Here we identified an atypical EMT while characterizing a population of mesenchymal cells in Huh7.5 hepatoma cell cultures. Cells with distinct morphology appeared during geneticin treatment of Huh7.5 cultures. Molecular characterization of geneticin resistant Huh7.5M cells confirmed EMT. Huh7.5M cells expressed cancer stem cell markers. p38MAPK and ERK1/2 were substantially activated in Huh7.5M cells. Their Inhibition elevated E-Cadherin expression with concerted suppression of Vimentin and anchorage independent growth in Huh7.5M cells. TGFβ could not induce EMT in Huh7.5 cultures, but enriched mesenchymal populations, similar to geneticin. Huh7.5M cells formed more aggressive solid tumors, primarily comprising cells with epithelial morphology, in nude mice. Canonical EMT-TFs did not participate in this atypical EMT, indicating that the established canonical EMT-TFs do not drive every EMT and there is a dire need to identify additional factors. The system that we characterized is a unique model to study EMT, MET and biphasic TGFβ signaling in HCC and offers considerable potential to facilitate more insightful studies on deeper questions in tumor metastasis.

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10.1038/srep26282Licence: CC BY

Publisher version (open access)Final published version, 1 MBLicence: CC BY

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