肺癌是台灣2003年在癌症相關死亡原因中排名位居第二位的癌症，然而在2004年肺癌已經躍升為第一位，因此發展新的分子標的或許可以為這種致命疾病提供新的治療方法。LKB1，一個絲胺酸/酥胺酸激

Lung cancer is the second leading cause of cancer-related death in Taiwan in 2003. However, lung cancer has become the first in 2004. Discovering the new molecular targets may provide new methods for the treatments of this devastating disease. LKB1, a serine/threonine kinase, is a new tumor suppressor gene with spontaneous mutations and/or deletions found in human cancers. Reports have recently demonstrated that LKB1 inactivating mutations in lung adenocarcinomas of sporadic origin, including primary tumors and lung cancer cell lines. In this study, we investigated LKB1 gene inactivation frequencies in 110 Taiwan patients with non-small cell lung carcinomas (NSCLC) and 7 lung cancer cell lines. LKB1 inactivation was screened by polymerase chain reaction (PCR), sequencing, co-amplification and loss of heterozygosity (LOH) analysis. In addition, LKB1 expressions were determined in clinical samples by immunohistochemistry (IHC) and in cell lines by reverse-transcriptase PCR and western blot analysis. The results showed five out of 110 (4.5%) patients with LKB1 gene exon 8 deletions. Two out these 5 patients were also found with exon 7 deletions. An identical mutation at codon 354 (Phe to Leu) were found in 4 out of 65 (6.2%) patients. The nature of this mutation was found to be a new LKB1 polymorphism by single strand conformation polymorphism (SSCP) assay and sequencing analysis after compared to normal controls. Various point mutations were also found in 3 out of 7 cell lines. In addition, 11 out of 81 (13.6%) patients were found with LOH. Finally, reduced expressions of LKB1 were observed in lung cancer clinical samples. These data suggest that LKB1 may be a tumor suppressor gene that involved in the carcinogenesis of NSCLC.

Abstract in Chinese…..…………………..………………………………………… i
Abstract in English……...………………………………………………………….. ii
I. Introduction…………………………………………………………………...... 1
1. Lung cancer………………………………………………………………........ 1
1-1. Histopathology of lung cancer………………………………………........ 2
1-1-1. SCLC……………………………………………………………....... 2
1-1-2. NSCLC……………………………………………………………… 2
1-1-2-1. Squamous cell carcinomas (SCCs)…………………………….. 3
1-1-2-2. Adenocarcinomas (LADs)…………………………………........ 3
1-1-2-3. Large cell carcinomas (LCCs)…………………………………. 4
1-2. Molecular pathogenesis of lung cancer………………………………….. 4
1-3. Prevention of lung cancer……………………………………………....... 5
2. Serine/threonine kinase 11 (LKB1/STK11)………………………………....... 6
2-1. PJS……………………………………………………………………….. 7
2-2. Functions of LKB1………………………………………………………. 7
2-2-1. LKB1 involvement in cell polarity, development and Wnt signaling……………………………………………………………………. 9
2-2-2. LKB1 in cell energy metabolism……………………………………. 10
2-2-3. LKB1 in chromatin remodeling…………………………………...... 13
2-2-4. LKB1 in cell cycle arrest and apoptosis…………………………….. 15
2-2-5. LKB1 interacting proteins………………………………………....... 17
3. LKB1 and cancers.......……………………………………………………....... 17
3-1. LKB1 and lung cancer…………………………………………………… 18
II. Specific Aims…………………………………………………………………... 21
III. Materials and Methods…………………………………………………………. 22
1. Tumor samples and cell lines…………………………………………………. 22
2. DNA extraction….............................................................................................. 23
2-1. For formaldehyde fixed tissue………………............................................ 23
2-1-1. QIAamp

Department of Health, Executive Yuan, Taiwan, R.O.C. http://www.doh.gov.tw/cht/ index.aspx

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