Activation of v-Myb Avian Myeloblastosis Viral Oncogene Homolog-Like2 (MYBL2)-LIN9 Complex Contributes to Human Hepatocarcinogenesis and Identifies a Subset of Hepatocellular Carcinoma with Mutant p53
Activation of v-Myb Avian Myeloblastosis Viral Oncogene Homolog-Like2 (MYBL2)-LIN9 Complex Contributes to Human Hepatocarcinogenesis and Identifies a Subset of Hepatocellular Carcinoma with Mutant p53
复制标题
DOI：
10.1002/hep.24174
复制
发表时间：
2011-04-01
期刊：
影响因子：
13.5
通讯作者：
Pascale, Rosa M.
中科院分区：
文献类型：
--
作者：
Calvisi, Diego F.;Simile, Maria M.;Pascale, Rosa M.
v-Myb禽成髓细胞瘤病毒癌基因同源物样2 B-Myb（MYBL 2）基因的上调发生在人肝细胞癌（HCC）中，并与啮齿动物肝癌发生的更快进展相关。我们评估了不同的人类HCC预后亚型（根据患者生存时间定义）中MYBL 2和MYBL 2相关基因的激活，以及p53状态与MYBL 2活性的关系。与预后较好的HCC（HCCB）相比，预后较差的HCC（HCCP）中MYBL 2、E2 F1-DP 1、失活视网膜母细胞瘤蛋白（pRB）和细胞周期蛋白B1的总蛋白和磷酸化蛋白水平最高。在HCCP中，出现最高的LIN 9-MYBL 2复合物（LINC）和最低的无活性LIN 9-p130复合物水平。MYBL 2与HCC基因组不稳定性、增殖和微血管密度呈正相关，与凋亡呈负相关。在具有突变型p53的HCC中较高的MYBL 2/LINC活化与在携带野生型p53的HCC中LINC失活形成对比。小干扰RNA（siRNA）介导的MYBL 2/LINC沉默在HCC细胞系中以相似水平降低增殖、诱导凋亡和DNA损伤，而与p53状态无关。然而，MYBL 2/LINC沉默与阿霉素诱导的DNA损伤的关联在p53（-/-）Huh 7和Hep 3B细胞中引起比在p53（+/+）Huh 6和HepG 2细胞中更强的生长抑制。阿霉素在p53（+/+）细胞系中触发LIN 9从MYBL 2解离，并在p53（-/-）细胞中增加MYBL 2-LIN 9复合物。阿霉素诱导的MYBL 2与LIN 9的解离导致p53（+/+）细胞系中p21（WAF 1）上调，但在p53（-/-）细胞系中没有。抑制p53或p21（WAF 1）基因消除DNA损伤反应，增强细胞凋亡，并抑制阿霉素处理的携带p53（+/+）细胞的生长。结论：我们表明MYBL 2激活对人类HCC进展至关重要。特别地，我们的数据表明MYBL 2-LIN 9复合物的完整性有助于DNA损伤的p53（-/-）细胞的存活。因此，MYBL 2抑制可以代表用于治疗具有突变的p53的人HCC的有价值的佐剂。（肝脏学2011;53：1226-1236）
Up-regulation of the v-Myb avian myeloblastosis viral oncogene homolog-like2 B-Myb (MYBL2) gene occurs in human hepatocellular carcinoma (HCC) and is associated with faster progression of rodent hepatocarcinogenesis. We evaluated, in distinct human HCC prognostic subtypes (as defined by patient survival length), activation of MYBL2 and MYBL2-related genes, and relationships of p53 status with MYBL2 activity. Highest total and phosphorylated protein levels of MYBL2, E2F1-DP1, inactivated retinoblastoma protein (pRB), and cyclin B1 occurred in HCC with poorer outcome (HCCP), compared to HCC with better outcome (HCCB). In HCCP, highest LIN9-MYBL2 complex (LINC) and lowest inactive LIN9-p130 complex levels occurred. MYBL2 positively correlated with HCC genomic instability, proliferation, and microvessel density, and negatively with apoptosis. Higher MYBL2/LINC activation in HCC with mutated p53 was in contrast with LINC inactivation in HCC harboring wildtype p53. Small interfering RNA (siRNA)-mediated MYBL2/LINC silencing reduced proliferation, induced apoptosis, and DNA damage at similar levels in HCC cell lines, irrespective of p53 status. However, association of MYBL2/LINC silencing with doxorubicin-induced DNA damage caused stronger growth restraint in p53(-/-) Huh7 and Hep3B cells than in p53(+/+) Huh6 and HepG2 cells. Doxorubicin triggered LIN9 dissociation from MYBL2 in p53(+/+) cell lines and increased MYBL2-LIN9 complexes in p53(-/-) cells. Doxorubicin-induced MYBL2 dissociation from LIN9 led to p21(WAF1) up-regulation in p53(+/+) but not in p53(-/-) cell lines. Suppression of p53 or p21(WAF1) genes abolished DNA damage response, enhanced apoptosis, and inhibited growth in doxorubicin-treated cells harboring p53(+/+). Conclusion: We show that MYBL2 activation is crucial for human HCC progression. In particular, our data indicate that MYBL2-LIN9 complex integrity contributes to survival of DNA damaged p53(-/-) cells. Thus, MYBL2 inhibition could represent a valuable adjuvant for treatments against human HCC with mutated p53. (HEPATOLOGY 2011;53:1226-1236)