Bandyopadhyay Sucharita, Pai Sudha K, Hirota Shigeru, Hosobe Sadahiro, Tsukada Taisei, Miura Kunio, Takano Yukio, Saito Ken, Commes Therese, Piquemal David, Watabe Misako, Gross Steven, Wang Ying, Huggenvik Jodi, Watabe Kounosuke
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA.
Cancer Res. 2004 Nov 1;64(21):7655-60. doi: 10.1158/0008-5472.CAN-04-1623.
PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown. Recently, a microarray analysis identified the Drg-1 gene (differentiation related gene 1) as one of the potential targets of PTEN. The Drg-1 gene has been shown to suppress tumor metastasis in animal models of prostate and colon cancer, and the expression of this gene is significantly reduced with advancement of prostate and breast cancers in clinical setting. In this study, we explored the possibility that PTEN controls tumor metastasis by regulating the expression of the Drg-1 gene. Our results indicate that overexpression of PTEN significantly augments the endogenous expression of Drg-1 protein, whereas inhibition of PTEN by small interfering RNA decreases Drg-1 in a dose- and time-dependent manner. We also found that the control of the Drg-1 gene by PTEN seems to be at the transcriptional level, and that a phospho-Akt inhibitor restores the Drg-1 expression, indicating that PTEN controls Drg-1 by an Akt-dependent pathway. Consistent with these results, our immunohistochemical analysis revealed that PTEN expression correlates significantly with Drg-1 in both prostate and breast cancer cases. Furthermore, combination of the two markers, PTEN and Drg-1, emerged as a significantly better predictor of prostate and breast cancer patient survival than either marker alone.
第10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）已被证实在多种癌症中失活，该基因作为肿瘤抑制因子的作用已得到充分确立。另一方面，近期动物研究结果以及临床证据表明，PTEN也参与肿瘤转移抑制。尽管已知PTEN在控制细胞生长和凋亡中起关键作用，但PTEN如何发挥转移抑制功能在很大程度上仍不清楚。最近，一项微阵列分析确定分化相关基因1（Drg-1）是PTEN的潜在靶点之一。在前列腺癌和结肠癌动物模型中，Drg-1基因已被证明可抑制肿瘤转移，在临床环境中，随着前列腺癌和乳腺癌的进展，该基因的表达显著降低。在本研究中，我们探讨了PTEN通过调节Drg-1基因的表达来控制肿瘤转移的可能性。我们的结果表明，PTEN的过表达显著增强了Drg-1蛋白的内源性表达，而小干扰RNA对PTEN的抑制则以剂量和时间依赖的方式降低了Drg-1的表达。我们还发现，PTEN对Drg-1基因的调控似乎在转录水平，并且一种磷酸化Akt抑制剂可恢复Drg-1的表达，这表明PTEN通过Akt依赖途径控制Drg-1。与这些结果一致，我们的免疫组织化学分析显示，在前列腺癌和乳腺癌病例中，PTEN表达与Drg-1显著相关。此外，与单独使用任何一种标志物相比，PTEN和Drg-1这两种标志物联合使用对前列腺癌和乳腺癌患者生存的预测效果明显更好。
