Dib Amel, Peterson Timothy R, Raducha-Grace Laura, Zingone Adriana, Zhan Fenghuang, Hanamura Ichiro, Barlogie Bart, Shaughnessy John, Kuehl W Michael
Genetics Branch, Center for Cancer Research, National Cancer Institute, Naval Hospital, Bldg 8, Rm 5101, Bethesda, MD20889-5105, USA.
Department of Biology, Masssachusetts Institutes of Technology, Whitehead Institute, 9 Cambridge Center, Rm 359, MA02142, USA.
Cell Div. 2006 Oct 18;1:23. doi: 10.1186/1747-1028-1-23.
A high proliferative capacity of tumor cells usually is associated with shortened patient survival. Disruption of the RB pathway, which is critically involved in regulating the G1 to S cell cycle transition, is a frequent target of oncogenic events that are thought to contribute to increased proliferation during tumor progression. Previously, we determined that p18INK4c, an essential gene for normal plasma cell differentiation, was bi-allelically deleted in five of sixteen multiple myeloma (MM) cell lines. The present study was undertaken to investigate a possible role of p18INK4c in increased proliferation of myeloma tumors as they progress.
Thirteen of 40 (33%) human myeloma cell lines do not express normal p18INK4c, with bi-allelic deletion of p18 in twelve, and expression of a mutated p18 fragment in one. Bi-allelic deletion of p18, which appears to be a late progression event, has a prevalence of about 2% in 261 multiple myeloma (MM) tumors, but the prevalence is 6 to 10% in the 50 tumors with a high expression-based proliferation index. Paradoxically, 24 of 40 (60%) MM cell lines, and 30 of 50 (60%) MM tumors with a high proliferation index express an increased level of p18 RNA compared to normal bone marrow plasma cells, whereas this occurs in only five of the 151 (3%) MM tumors with a low proliferation index. Tumor progression is often accompanied by increased p18 expression and an increased proliferation index. Retroviral-mediated expression of exogenous p18 results in marked growth inhibition in three MM cell lines that express little or no endogenous p18, but has no effect in another MM cell line that already expresses a high level of p18.
Paradoxically, although loss of p18 appears to contribute to increased proliferation of nearly 10% of MM tumors, most MM cell lines and proliferative MM tumors have increased expression of p18. Apart from a small fraction of cell lines and tumors that have inactivated the RB1 protein, it is not yet clear how other MM cell lines and tumors have become insensitive to the anti-proliferative effects of increased p18 expression.
肿瘤细胞的高增殖能力通常与患者生存期缩短相关。RB通路的破坏在调控细胞从G1期到S期的细胞周期转换中起关键作用，是致癌事件的常见靶点，被认为在肿瘤进展过程中促进了增殖增加。此前，我们确定p18INK4c是正常浆细胞分化的必需基因，在16个多发性骨髓瘤（MM）细胞系中的5个中发生了双等位基因缺失。本研究旨在探讨p18INK4c在骨髓瘤肿瘤进展过程中增殖增加方面可能发挥的作用。
40个人类骨髓瘤细胞系中有13个（33%）不表达正常的p18INK4c，其中12个p18发生双等位基因缺失，1个表达突变的p18片段。p18的双等位基因缺失似乎是一个晚期进展事件，在261个多发性骨髓瘤（MM）肿瘤中的发生率约为2%，但在基于高表达的增殖指数的50个肿瘤中的发生率为6%至10%。矛盾的是，40个MM细胞系中的24个（60%）以及50个具有高增殖指数的MM肿瘤中的30个（60%）与正常骨髓浆细胞相比，p18 RNA表达水平升高，而在151个低增殖指数的MM肿瘤中只有5个（3%）出现这种情况。肿瘤进展通常伴随着p18表达增加和增殖指数升高。逆转录病毒介导的外源性p18表达在3个几乎不表达或不表达内源性p18的MM细胞系中导致显著的生长抑制，但在另一个已经高水平表达p18的MM细胞系中没有作用。
矛盾的是，尽管p18缺失似乎导致了近10%的MM肿瘤增殖增加，但大多数MM细胞系和增殖性MM肿瘤的p18表达增加。除了一小部分使RB1蛋白失活的细胞系和肿瘤外，目前尚不清楚其他MM细胞系和肿瘤如何对p18表达增加的抗增殖作用变得不敏感。
