TGF beta1 and related-Smads contribute to pulmonary metastasis of hepatocellular carcinoma in mice model
Recent studies indicate that Transforming Growth Factor beta (TGF β) correlated with pulmonary metastasis of cancers. However, the correlation between TGF β and pulmonary metastasis of hepatocellular carcinoma (HCC) is till unknown.
We detected the in vitro and in vivo expression levels of TGF β1/Smads by Real-time PCR and Western blot in MHCC97-H and MHCC97–L cell lines, which are HCC cell lines and have higher and lower pulmonary metastatic potential respectively.
TGF β1 mRNA level in MHCC97-L tumors were higher than that in MHCC97-H tumors, (2.81±1.61 vs. 1.24±0.96, P=0.002), TGF β1 protein level in MHCC97-L tumors were also higher than that in MHCC97-H tumors (1.37±0.95 vs. 0.32±0.22, P<0.001). In addition, the TGF β1 mRNA level positively correlated with pulmonary metastasis, and the relations between TGF β1 and Smads were also found (R2=0.12 and 0.40, respectively).
Our results suggest that TGF β/ Smads promote pulmonary metastasis of HCC.
- Ono T, Yamanoi A, Nazmy E, Assal O, Kohno H, Nagasue N: Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: meta analysis of three randomized controlled trials. Cancer 2001, 91:2378–2385. CrossRef
- Kurokawa Y, Matoba R, Takemasa I, Nagano H, Dono K, Nakamori S, Umeshita K, Sakon M, Ueno N, Oba S, et al.: Monden MMolecular-based prediction of early recurrence in hepatocellular carcinoma. J Hepatol 2004, 41:284–291. CrossRef
- Lai EC, Fan ST, Lo CM, Chu KM, Liu CL, Wong J: Hepatic resection for hepatocellular carcinoma. An audit of 343 patients. Ann Surg 1995, 221:291–298. CrossRef
- Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, et al.: Predicting hepatitis B virus–positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003, 9:416–423. CrossRef
- Genda T, Sakamoto M, Ichida T, Asakura H, Hirohashi S: Cell motility mediated by rho and rho-associated protein kinase plays a critical role in intrahepatic metastasis of human hepatocellular carcinoma. Hepatology 1999, 30:1027–1036. CrossRef
- Nakamura T, Kimura T, Umehara Y, Suzuki K, Okamoto K, Okumura T, Morizumi S, Kawabata T, Komiyama A: Long-term survival after report resection of pulmonary metastases from hepatocellular carcinoma: report of two cases. Surg Today 2005, 35:890–892. CrossRef
- Giannelli G, Fransvea E, Marinosci F, Bergamini C, Colucci S, Schiraldi O, Antonaci S: Transforming growth factor-beta1 triggers hepatocellular carcinoma invasiveness via alpha3beta1 integrin. Am J Pathol 2002, 161:183–193. CrossRef
- Lyer S, Wang ZG, Akhtari M, Zhao W, Seth P: TargetingTGFbeta signaling for cancer therapy. Cancer Biol Ther 2005, 4:261–266. CrossRef
- Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E: TGFbeta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 1996, 10:2462–2477. CrossRef
- Kinnman N, Andersson U, Hultcrantz C: In situ expression of transforming growth factor-beta 1–3, latent transforming growth factor-beta binding protein and tumor necrosis factor-alpha in liver tissue from patients with chronic hepatitis C. Scand J Gastroenterol 2000, 35:1294–1300. CrossRef
- Rubtsov YP, Rudensky AY: TGFβ signalling in control of T-cell-mediated self-reactivity. Nature Immunol 2007, 7:443–453. CrossRef
- Itoh S, Itoh F, Goumans MJ,PTD: Signaling of transforming growth factor-b family members through Smad proteins. Eur J Biochem 2000, 267:6954–6967. CrossRef
- Welm AL: TGFβ primes breast tumor cells for metastasis. Cell 2008, 133:27–28. CrossRef
- Song BC, Chung YH, Kim JA, Choi WB, Suh DD, Pyo SI, Shin JW, Lee HC, Lee YS, Suh DJ: Transforming growth factor-beta1 as a useful serologic marker of small hepatocellular carcinoma. Cancer 2002, 94:175–180. CrossRef
- Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S: Laminin-5 With Transforming Growth Factor-β1 Induces Epithelial to Mesenchymal Transition in Hepatocellular Carcinoma. Gastroenterology 2005, 129:1375–1383. CrossRef
- Grasl-Kraupp B, Rossmanith W, Ruttkay-Nedecky B, Mullauer L, Kammerer B, Bursch W, Schulte-Hermann R: Levels of transforming growth factor β and transforming growth factor β receptors in rat liver during growth, regression by apoptosis and neoplasia. Hepatology 1998, 28:717–726. CrossRef
- Jaskiewicz K, Chasen MR: Differential expression of transforming growth factor β, adhesions molecules and integrins in primary, metastatic liver tumors and in liver cirrhosis. Anticancer Res 1995, 15:559–562.
- Yuen MF, Norris S, Evans LW, Langley PG, Hughes RD: Transforming growth factor-β1, activin and follistatin in patients with hepatocellular carcinoma and patients with alcoholic cirrhosis. Scand J Gastroenterol 2002, 37:233–238. CrossRef
- Kim YJ, Lee HS, Im JP, Min BH, Kim HD, Jeong JB, Yoon JH, Kim CY, Kim MS, Kim JY, et al.: Association of transforming growth factor-β1 gene polymorphisms with a hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection. Exp Mol Med 2003, 35:196–202.
- Li Y, Tang Y, Ye L, Liu B, Liu K, Chen J, Xue Q: Establishment of a hepatocellular carcinoma cell line with unique metastatic characteristics through in vivo selection and screening for metastasis-related genes through cDNA microarray. J Cancer Res Clin Oncol 2003, 129:43–51. CrossRef
- Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Chen J, Gao DM, Bao WH: Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol 2001, 7:630–636.
- Carey KD, Garton AJ, Romero MS, Kahler J, Thomson S, Ross S, Park F, Haley JD, Gibson N, Sliwkowski MX: Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res 2006, 66:8163–8171. CrossRef
- Lin JK, Chou CK: In Vitro apoptosis in the human hepatoma cell line induced by Transforming Growth Factor beta1. Cancer Res 1992, 52:385–388.
- Wu SP, Sun LZ, Willson JK, Humphrey L, Kerbel R, Brattain MG: Repression of autocrine transforming growth factor beta 1 and beta 2 in quiescent CBS colon carcinoma cells leads to progression of tumorigenic properties. Cell Growth Diff 1993, 4:115–123.
- Wu SP, Theodorescu D, Kerbel RS, Willson JK, Mulder KM, Humphrey LE, Brattain MG: TGF-beta 1 is an autocrine-negative growth regulator of human colon carcinoma FET cells in vivo as revealed by transfection of an antisense expression vector. J Cell Biol 1992, 116:187–196. CrossRef
- Fransvea E, Angelotti U, Antonaci S, Giannelli G: Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology 2008, 47:1557–1566. CrossRef
- Derynck R, Akhurst RJ, Balmain A: TGF-β signaling in tumor suppression and cancer progression. Nat Genet 2001, 29:117–129. CrossRef
- Katabami K, Mizuno H, Sano R, Saito Y, Ogura M, Itoh S, Tsuji T: Transforming growth factor-β1 upregulates transcription of a3 integrin gene in hepatocellular carcinoma cells via Ets-transcription factor-binding motif in the promoter region. Clin Exp Metastas 2005, 22:539–548. CrossRef
- Littlepage LE, Egeblad M, Werb Z: Coevolution of cancer and stromal cellular responses. Cancer Cell 2005, 7:499–500. CrossRef
- Bhowmick NA, Ghiassi M, Aakre M, Brown K, Singh V, Moses HL: TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest. PNAS 2003, 100:15548–15553. CrossRef
- Wahl SM, Allen JB, Weekst BS HLW, Klotmant PE: Transforming growth factor 1–3 enhances integrin expression and type IV collagenase secretion in human monocytes. PNAS 1993, 90:15548–15553. CrossRef
- Li GC, Ye QH, Xue YH, Sun HJ, Zhou HJ, Ren N, Jia HL, Shi J, Wu JC, Dai C, et al.: Human mesenchymal stem cells inhibit metastasis of a hepatocellular carcinoma model using the MHCC97-H cell line. Cancer Sci 2010, 101:2546–2553. CrossRef
- TGF beta1 and related-Smads contribute to pulmonary metastasis of hepatocellular carcinoma in mice model
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Journal of Experimental & Clinical Cancer Research
- Online Date
- November 2012
- Online ISSN
- BioMed Central
- Additional Links
- Hepatocellular carcinoma
- Transforming growth factor beta
- Author Affiliations
- 1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China
- 2. GaoXin Hospital, Xi’an JiaoTong University, Xi’an, Shanxi Province, China