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문혁(내과학교실) Gastroenterology
등록일 : 2017-07-31 오전 9:48:00       조회 : 178
첨   부 :
제1저자 문혁(Hyuk Moon, 내과학교실 지도교수 한광협, 소화기병연구소, BK21)
교신저자 노원상(Simon Weonsang Ro, 소화기병연구소, 연구조교수)

Gastroenterology. 2017 Jul 19. pii: S0016-5085(17)35920-6. doi: 10.1053/j.gastro.2017.07.014. [Epub ahead of print]
Transforming Growth Factor Beta Promotes Liver Tumorigenesis in Mice via Upregulation of Snail.

Moon H1, Ju HL2, Chung SI2, Cho KJ1, Eun JW3, Nam SW3, Han KH4, Calvisi DF5, Ro SW6.
Author information
1
Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, South Korea; Brain Korea 21 Project for Medical Science College of Medicine, Yonsei University, Seoul 03722, South Korea.
2
Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, South Korea.
3
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
4
Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea.
5
Institute of Pathology, University Medicine Greifswald, Greifswald 17475, Germany.
6
Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, South Korea. Electronic address: simonr@yuhs.ac.

Abstract
BACKGROUND & AIMS:
Transforming growth factor beta (TGFB) suppresses early stages of tumorigenesis, but also contributes to migration and metastasis of cancer cells. A large number of human tumors contain mutations that inactivate its receptors, or downstream proteins such as Smad transcription factors, indicating that the TGFB signaling pathway prevents tumor growth. We investigated the effects of TGFB inhibition on liver tumorigenesis in mice.
METHODS:
C57BL/6 mice received hydrodynamic tail injections of transposons encoding HRASG12V and a short hairpin RNA (shRNA) to downregulate p53, or those encoding HRASG12V and MYC, or those encoding HRASG12V and TAZS89, to induce liver tumor formation; mice were also given injections of transposons encoding SMAD7 or shRNA against SMAD2, SMAD3, SMAD4, or SNAI1 (Snail), with or without ectopic expression of Snail. Survival times were compared and livers were weighted and examined for tumors. Liver tumor tissues were analyzed by quantitative reverse-transcription PCR, RNA-sequencing, immunoblots, and immunohistochemistry. We analyzed gene expression levels in human hepatocellular carcinoma (HCC) samples deposited in The Cancer Genome Atlas. A cell proliferation assay was performed using human liver cancer cell lines (HepG2 and Huh7) stably expressing Snail or shRNA against Snail.
RESULTS:
TGFB inhibition via overexpression of SMAD (or knockdown of SMAD2, SMAD3, or SMAD4) consistently reduced formation and growth of liver tumors in mice that expressed activated RAS plus shRNA against p53, or in mice that expressed activated RAS and TAZ. TGFB signaling activated transcription of the Snail gene in liver tumors induced by HRASG12V and shRNA agasint p53, and by activated RAS and TAZ. Knockdown of Snail reduced liver tumor formation in both tumor models. Ectopic expression of Snail restored liver tumorigenesis suppressed by disruption of TGFB signaling. In human HCC, Snail expression correlated with TGFB activation. Ectopic expression of Snail increased cellular proliferation, whereas Snail knockdown led to reduced proliferation in human HCC cells CONCLUSIONS: In analyses of transgenic mice, we found TGFB signaling to be required for formation of liver tumors upon expression of activated RAS and shRNA downregulating p53, and upon expression of activated RAS and TAZ. Snail is the TGFB target that is required for hepatic tumorigenesis in these models.
조보람(생리학교실) Sci Rep 2017-08-07
Naina Adren Pinto(진단검사의학교실) Oncotarget 2017-07-17