TALIN-1 METASTASIS SUPPRESSOR IN LUNG CANCER

肺癌是由一系列遗传事件引起的多因素疾病，包括细胞周期检查点和进展、细胞增殖和染色体稳定性的变化，这导致原发性癌的发展。在原发性肿瘤形成后，正常细胞粘附和运动性的变化随后允许这些肿瘤细胞从原始肿瘤中逃逸，迁移到继发部位，并重新生长。在原发性肿瘤中获得这种能力常常导致临床上无法治愈的疾病，并且这些继发性肿瘤或转移是肺癌患者死亡率和发病率的重要因素。9号染色体9 p21位置上的几种遗传病变与肺癌有关。其中包括粘着斑蛋白Talin-1， 参与细胞粘附和运动。Talin-1水平在某些肺癌细胞中降低。 待评估的假设是Talin-1的失调导致改变的细胞粘附，从而导致原发性肿瘤中细胞的锚定非依赖性生长。这种表型的获得增加了这些细胞的侵袭力，并导致转移性肺癌的发展。具体目标。这一假设将通过以下方式来解决：（1）确定肺癌细胞中Talin-1在基因、mRNA和蛋白水平上缺陷的分子基础;（2）确定Talin-1在肺癌细胞粘附、迁移和侵袭中的作用，特别强调肺癌细胞在模拟体内细胞环境的三维培养基质中的行为;以及（3）将这些研究扩展到代表肺癌的每个组织学类别的广泛的肺癌细胞系组， 以前未知的转移性肺癌的一般特征将被识别。 意义这些研究将提供深入了解肺癌进展的分子和细胞机制，并确定Talin-1是否是肺癌转移的抑制因子。这些研究还将导致发展新的预后指标和治疗转移性肺癌的治疗策略。

Lung cancer is a multifactorial disease caused by a cascade of genetic events, including changes in cell cycle checkpoint and progression, cell proliferation, and chromosome stability, which leads to the development of a primary carcinoma. After establishment of the primary tumor, changes in normal cell adhesion and motility subsequently allow these tumor cells to escape from the original tumor, migrate to secondary sites, and grow anew. The acquisition of this capacity in the primary tumor frequently results in clinically incurable disease, and these secondary tumors, or metastases, are a significant contributor to mortality and morbidity in lung cancer patients. Several genetic lesions on chromosome 9 at position 9p21 have been associated with lung cancer. Among these is the focal adhesion protein Talin-1, which is involved in cell adhesion and motility. Talin-1 levels are decreased in certain lung cancer cells. The HYPOTHESIS to be evaluated is that dysregulation of Talin-1 leads to altered cell adhesion leading to anchorage-independent growth of cells in the primary tumor. Acquisition of this phenotype then increases the invasiveness of these cells and results in the development of metastatic lung cancer. SPECIFIC AIMS. This hypothesis will be addressed by (1) determining the molecular basis for the Talin-1 deficiency at the gene, mRNA, and protein levels in lung cancer cells; (2) determining the role of Talin-1 in lung cancer cell adhesion, migration, and invasion, with particular emphasis on the behavior of lung cancer cells in three-dimensional culture matrices that mimic the cellular environment in vivo; and (3) extending these studies to a broad panel of lung cancer cell lines representing each histological class of lung cancer so that previously unknown general features of metastatic lung cancer will be identified. SIGNIFICANCE. These studies will provide insight into the molecular and cellular mechanisms of lung cancer progression and determine whether Talin-1 is a suppressor of metastasis in lung cancer. These studies will also lead to the development of new prognostic indicators and therapeutic strategies for treatment of metastatic lung cancer.