生物谷報(bào)道：在9月4日的PNAS雜志的網(wǎng)絡(luò)版上公示了一篇由香港大學(xué)外科學(xué)系和肝病研究中心的范上逵教授,、Siu Tim Cheung教授與來(lái)自美國(guó)加州大學(xué)和斯坦福大學(xué)的同事聯(lián)合發(fā)表的一篇有關(guān)肝臟腫瘤研究的最新成果，論文題為“Distinct pathways of genomic progression to benign and malignant tumors of the liver”,。
在這項(xiàng)研究中，研究組在小鼠模型中利用通常與人類肝臟腫瘤相關(guān)的遺傳損傷重構(gòu)了肝細(xì)胞癌和腺癌的genetic progression,。研究人員通過(guò)原癌基因MET轉(zhuǎn)基因或水動(dòng)力轉(zhuǎn)染MET和其他一些基因到成熟小鼠肝臟中，從而觸發(fā)腫瘤的形成,。
肝細(xì)胞癌的發(fā)生需要MET和活潑版本的β-catenin的合作,。相反,，腺癌則是因?yàn)镸ET和轉(zhuǎn)錄因子HNF1 的缺陷信號(hào)途徑相互作用所導(dǎo)致的。
根據(jù)這些發(fā)現(xiàn),，研究人員揭露出了由MET編碼的蛋白質(zhì)－酪氨酸激酶活性與β-catenin的活化突變?cè)谝环N人類肝細(xì)胞癌中的一種同步、一致性,。
盡管活潑的β－catenin 仍然存在，但MET轉(zhuǎn)基因的失活卻能導(dǎo)致肝細(xì)胞癌的衰退,。但是，腫瘤最終會(huì)在缺少M(fèi)ET表達(dá)的情況下復(fù)發(fā),。其原因可能是與活化的β-catenin合作的一個(gè)或更多分子事件的發(fā)生替代了MET的作用,。
這項(xiàng)研究的結(jié)果增加了對(duì)肝癌發(fā)生的了解，并且構(gòu)建出的小鼠模型將能夠用于將來(lái)進(jìn)一步研究肝癌腫瘤發(fā)生和前臨床檢測(cè),。而且，研究還確定出了一種亞型的人類肝細(xì)胞癌,，這種癌癥可能對(duì)直接靶向Met和Wnt信號(hào)途徑的聯(lián)合藥物治療方法敏感,。
范上逵教授是向廣大學(xué)外科學(xué)系肝膽胰外科的首席教授。他對(duì)肝細(xì)胞癌,、乙型肝炎、肝內(nèi)結(jié)石,、急性膽管胰腺炎和肝臟移植等方向進(jìn)行了廣泛深入的研究。
去年9月,，來(lái)自香港大學(xué)肝臟疾病研究中心及外科系的研究人員發(fā)現(xiàn)了肝細(xì)胞癌中腫瘤血管新生（tumour angiogenesis）過(guò)程中富含半胱氨酸的分泌性蛋白(secreted protein acidic and rich in cysteine, SPARC)和Hevin表達(dá)的作用。這一研究成果即將公布在影響因子為6.213的《the Journal of Pathology》雜志上,。
富含半胱氨酸的酸性分泌蛋白(secreted protein acidic and rich in cysteine,SPARC)曾被稱作骨連接蛋白(osteonectin,ON),、基底膜-40(BM-40)或43k蛋白,。SPARC和Hevin與腫瘤的發(fā)生和進(jìn)展相關(guān),，也與腫瘤的侵襲和轉(zhuǎn)移關(guān)系密切,，而且與某些腫瘤的臨床分期和預(yù)后相關(guān),。最近有研究表明Hevin和SPARC可以共同作用于抑制血管新生，但是它們?cè)诟渭?xì)胞癌（hepatocellular carcinoma,，HCC）方面的重大作用還不清楚,。
Cecilia Pik-Yuk Lau, MPhil等人主要針對(duì)在HCC血管新生和臨床病理學(xué)特征中SPARC和Hevin表達(dá)的共同作用進(jìn)行研究,。他們通過(guò)對(duì)在HCC樣品中表達(dá)的SPARC和Hevin蛋白，以及mRNA進(jìn)行免疫染色（immunostaining）,，免疫雜交和定量RT-PCR鑒定，發(fā)現(xiàn)SPARC和Hevin的mRNA水平在肝臟腫瘤中比正常的肝臟高的多,，而且腫瘤中SPARC和Hevin的mRNA水平密切相關(guān),。另外在腫瘤竇狀小管區(qū)域的SPARC蛋白也與HCC細(xì)胞中Hevin蛋白有極大的相互作用,。這些都說(shuō)明比較于正常肝臟，SPARC和Hevin在HCC是正調(diào)控的,，而且無(wú)論是mRNA還是蛋白水平都是內(nèi)部相關(guān)的（inter-related）,，除此之外,，SPRC和Hevin與HCC血管新生和腫瘤生長(zhǎng)也是密切相關(guān)。
原始出處：
Published online before print September 4, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0706578104
Medical Sciences
Distinct pathways of genomic progression to benign and malignant tumors of the liver
( -catenin | hepatocyte nuclear factor 1 | liver cancer | MET | mouse | hepatocellular carcinoma )
Aaron D. Tward *, Kirk D. Jones , Stephen Yant , Siu Tim Cheung ¶, Sheung Tat Fan ¶, Xin Chen ||, Mark A. Kay , Rong Wang **, and J. Michael Bishop *
*G. W. Hooper Foundation and Department of Microbiology and Immunology, Department of Pathology, ||Department of Biopharmaceutical Sciences, and **Departments of Anatomy and Surgery and the Pacific Vascular Research Laboratory, University of California, San Francisco, CA 94143; Departments of Pediatrics and Genetics, Stanford University, Stanford, CA 94305; and ¶Department of Surgery and Centre for the Study of Liver Disease, University of Hong Kong, Pok Fu Lam Road, Hong Kong, China
Contributed by J. Michael Bishop, July 12, 2007 (sent for review May 29, 2007)
We used several of the genetic lesions commonly associated with human liver tumors to reconstruct genetic progression to hepatocellular carcinoma and adenoma in mouse models. We initiated tumorigenesis with a transgene of the protooncogene MET or by hydrodynamic transfection of MET in combination with other genes into the livers of adult animals. Hepatocellular carcinoma in both instances arose from cooperation between MET and constitutively active versions of -catenin. In contrast, adenomas were produced by cooperation between MET and defective signaling through the transcription factor HNF1. Prompted by these findings, we uncovered a coincidence between activation of the protein-tyrosine kinase encoded by MET and activating mutations of -catenin in a subset of human hepatocellular carcinomas. Inactivation of MET transgenes led to regression of hepatocellular carcinomas despite the persistence of activated -catenin. The tumors eventually recurred in the absence of MET expression, however, presumably after the occurrence of one or more events that cooperated with activated -catenin in lieu of MET. These results offer insight into hepatic tumorigenesis, provide mouse models that should be useful in the further study of hepatic tumorigenesis and for preclinical testing, and identify a subset of human hepatocellular carcinomas that may be susceptible to combination therapy directed against Met and the Wnt signaling pathway.
