生物谷报道：在9月4日的PNAS杂志的网络版上公示了一篇由香港大学外科学系和肝病研究中心的范上逵教授、Siu Tim Cheung教授与来自美国加州大学和斯坦福大学的同事联合发表的一篇有关肝脏肿瘤研究的最新成果，论文题为“Distinct pathways of genomic progression to benign and malignant tumors of the liver”。
在这项研究中，研究组在小鼠模型中利用通常与人类肝脏肿瘤相关的遗传损伤重构了肝细胞癌和腺癌的genetic progression。研究人员通过原癌基因MET转基因或水动力转染MET和其他一些基因到成熟小鼠肝脏中，从而触发肿瘤的形成。
肝细胞癌的发生需要MET和活泼版本的β-catenin的合作。相反，腺癌则是因为MET和转录因子HNF1 的缺陷信号途径相互作用所导致的。
根据这些发现，研究人员揭露出了由MET编码的蛋白质－酪氨酸激酶活性与β-catenin的活化突变在一种人类肝细胞癌中的一种同步、一致性。
尽管活泼的β－catenin 仍然存在，但MET转基因的失活却能导致肝细胞癌的衰退。但是，肿瘤最终会在缺少MET表达的情况下复发。其原因可能是与活化的β-catenin合作的一个或更多分子事件的发生替代了MET的作用。
这项研究的结果增加了对肝癌发生的了解，并且构建出的小鼠模型将能够用于将来进一步研究肝癌肿瘤发生和前临床检测。而且，研究还确定出了一种亚型的人类肝细胞癌，这种癌症可能对直接靶向Met和Wnt信号途径的联合药物治疗方法敏感。
范上逵教授是向广大学外科学系肝胆胰外科的首席教授。他对肝细胞癌、乙型肝炎、肝内结石、急性胆管胰腺炎和肝脏移植等方向进行了广泛深入的研究。
去年9月，来自香港大学肝脏疾病研究中心及外科系的研究人员发现了肝细胞癌中肿瘤血管新生（tumour angiogenesis）过程中富含半胱氨酸的分泌性蛋白(secreted protein acidic and rich in cysteine, SPARC)和Hevin表达的作用。这一研究成果即将公布在影响因子为6.213的《the Journal of Pathology》杂志上。
富含半胱氨酸的酸性分泌蛋白(secreted protein acidic and rich in cysteine,SPARC)曾被称作骨连接蛋白(osteonectin,ON)、基底膜-40(BM-40)或43k蛋白。SPARC和Hevin与肿瘤的发生和进展相关，也与肿瘤的侵袭和转移关系密切，而且与某些肿瘤的临床分期和预后相关。最近有研究表明Hevin和SPARC可以共同作用于抑制血管新生，但是它们在肝细胞癌（hepatocellular carcinoma，HCC）方面的重大作用还不清楚。
Cecilia Pik-Yuk Lau, MPhil等人主要针对在HCC血管新生和临床病理学特征中SPARC和Hevin表达的共同作用进行研究。他们通过对在HCC样品中表达的SPARC和Hevin蛋白，以及mRNA进行免疫染色（immunostaining），免疫杂交和定量RT-PCR鉴定，发现SPARC和Hevin的mRNA水平在肝脏肿瘤中比正常的肝脏高的多，而且肿瘤中SPARC和Hevin的mRNA水平密切相关。另外在肿瘤窦状小管区域的SPARC蛋白也与HCC细胞中Hevin蛋白有极大的相互作用。这些都说明比较于正常肝脏，SPARC和Hevin在HCC是正调控的，而且无论是mRNA还是蛋白水平都是内部相关的（inter-related），除此之外，SPRC和Hevin与HCC血管新生和肿瘤生长也是密切相关。
原始出处：
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.
