Role of DLC1 tumor suppressor gene and MYC oncogene in pathogenesis of human hepatocellular carcinoma: potential prospects for combined targeted therapeutics (review).
Role of DLC1 tumor suppressor gene and MYC oncogene in pathogenesis of human hepatocellular carcinoma: potential prospects for combined targeted therapeutics (review).
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DOI：
10.3892/ijo.2012.1474
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发表时间：
2012-08
影响因子：
5.2
通讯作者：
Popescu NC
中科院分区：
文献类型：
--
作者：
Zimonjic DB;Popescu NC
肝细胞癌（HCC）是第三大癌症死亡原因，其发病率在全球范围内以惊人的方式增加。开发晚期和转移性肝癌的治愈性疗法是临床上的一个高度优先事项。HCC基因组是复杂和异质的;因此，鉴定复发性基因组和相关基因改变对于开发用于疾病的诊断、预后和靶向治疗的临床应用至关重要。本文着重介绍了最近的研究进展和我们的贡献，在确定和破译的作用，定义的遗传变异在肝癌的发病机制。已经在基因组重组位点鉴定了大量促进或抑制HCC细胞生长的基因。尽管存在多种遗传改变的累积，但单个染色体上的高度复发性变化可改变癌基因和肿瘤抑制基因（TSGs）的表达，其失调可能足以驱动正常肝细胞向恶性进展。HCC中基因组不平衡的独特且高度复发的模式包括含TSG的染色体8 p的DNA拷贝数的丢失（与杂合性丢失相关）和染色体8 q上的原癌基因的DNA拷贝数或区域扩增的获得。尽管8 p相对较小，但它携带了异常大量的TSG，而另一方面，几个癌基因沿着8 q分布。令人信服的证据表明，DLC 1，一个有效的TSG在8 p上，和MYC癌基因在8 q上发挥了关键作用，在人类肝癌的发病机制。在嵌合体小鼠模型中已经获得了它们在HCC发生中的作用的直接证据。DLC 1的敲低有助于MYC在体外诱导成肝细胞转化，并在体内发展为HCC。同时靶向肝癌发生中DLC 1和MYC功能的信号通路的治疗干预可能会导致肝癌治疗的进展。
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, and its incidence is increasing worldwide in an alarming manner. The development of curative therapy for advanced and metastatic HCC is a high clinical priority. The HCC genome is complex and heterogeneous; therefore, the identification of recurrent genomic and related gene alterations is critical for developing clinical applications for diagnosis, prognosis and targeted therapy of the disease. This article focuses on recent research progress and our contribution in identifying and deciphering the role of defined genetic alterations in the pathogenesis of HCC. A significant number of genes that promote or suppress HCC cell growth have been identified at the sites of genomic reorganization. Notwithstanding the accumulation of multiple genetic alterations, highly recurrent changes on a single chromosome can alter the expression of oncogenes and tumor suppressor genes (TSGs) whose deregulation may be sufficient to drive the progression of normal hepatocytes to malignancy. A distinct and highly recurrent pattern of genomic imbalances in HCC includes the loss of DNA copy number (associated with loss of heterozygosity) of TSG-containing chromosome 8p and gain of DNA copy number or regional amplification of protooncogenes on chromosome 8q. Even though 8p is relatively small, it carries an unusually large number of TSGs, while, on the other side, several oncogenes are dispersed along 8q. Compelling evidence demonstrates that DLC1, a potent TSG on 8p, and MYC oncogene on 8q play a critical role in the pathogenesis of human HCC. Direct evidence for their role in the genesis of HCC has been obtained in a mosaic mouse model. Knockdown of DLC1 helps MYC in the induction of hepatoblast transformation in vitro, and in the development of HCC in vivo. Therapeutic interventions, which would simultaneously target signaling pathways governing both DLC1 and MYC functions in hepatocarcinogenesis, could result in progress in the treatment of liver cancer.
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影响因子：
11.2
作者：
Cao Z;Fan-Minogue H;Bellovin DI;Yevtodiyenko A;Arzeno J;Yang Q;Gambhir SS;Felsher DW
通讯作者：
Felsher DW
影响因子：
3.7
作者：
EMI, M;FUJIWARA, Y;NAKAMURA, Y
通讯作者：
NAKAMURA, Y
影响因子：
3.7
作者：
Chan, Lo-Kong;Ko, Frankie Chi Fat;Yam, Judy Wai Ping
通讯作者：
Yam, Judy Wai Ping
影响因子：
56.9
作者：
BISHOP, JM
通讯作者：
BISHOP, JM
DOI：
10.1073/pnas.94.13.6770
发表时间：
1997-06-24
影响因子：
11.1
作者：
Finch, PW;He, X;Rubin, JS
通讯作者：
Rubin, JS