Anhui Province Key Laboratory of Molecular Medicine and Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, People's Republic of China.
J Interferon Cytokine Res. 2009 Oct;29(10):695-703. doi: 10.1089/jir.2009.0003.
Cervical cancer is the most common malignant disease responsible for the deaths of a large number of women in the developing world. Although certain strains of human papillomavirus (HPV) have been identified as the cause of this disease, events that lead to formation of malignant tumors are not fully clear. STAT3 is a major oncogenic transcription factor involved in the development and progression of a number of human tumors. However, the mechanisms that result in loss of control over STAT3 activity are not understood. Gene associated with Retinoid-Interferon-induced Mortality-19 (GRIM-19) is a tumor-suppressive protein identified using a genetic technique in the interferon/retinoid-induced cell death pathway. Here, we show that reduction in GRIM-19 protein levels occur in a number of primary human cervical cancers. Consequently, these tumors tend to express a high basal level of STAT3 and its downstream target genes. More importantly, using a surrogate model, we show that restoration of GRIM-19 levels reestablishes the control over STAT3-dependent gene expression and tumor growth in vivo. GRIM-19 suppressed the expression of tumor invasion- and angiogenesis-associated factors to limit tumor growth. This study identifies another major novel molecular pathway inactivated during the development of human cervical cancer.
宫颈癌是发展中国家导致大量女性死亡的最常见恶性疾病。虽然已经确定某些类型的人乳头瘤病毒（HPV）是导致这种疾病的原因，但导致恶性肿瘤形成的事件尚不完全清楚。STAT3 是一种主要的致癌转录因子，参与多种人类肿瘤的发生和发展。然而，导致 STAT3 活性失控的机制尚不清楚。与视黄酸干扰素诱导死亡相关蛋白 19（GRIM-19）相关的基因是通过干扰素/视黄酸诱导的细胞死亡途径中的遗传技术鉴定的肿瘤抑制蛋白。在这里，我们表明，在许多原发性人宫颈癌中，GRIM-19 蛋白水平降低。因此，这些肿瘤往往表达高水平的 STAT3 和其下游靶基因。更重要的是，我们使用替代模型表明，恢复 GRIM-19 水平可以重新建立对 STAT3 依赖性基因表达和体内肿瘤生长的控制。GRIM-19 抑制肿瘤侵袭和血管生成相关因子的表达，从而限制肿瘤生长。这项研究确定了人类宫颈癌发展过程中另一个主要的新型分子途径失活。
