Advances in molecular studies of lung cancer

1、 Advances in molecular studies of lung cancer Keywords: Survivin telomerase vascular endothelial growth factor hypoxia-inducible factor COX-2, 1 lung cancer Many molecular studies of lung cancer, but really as a marker for molecular diagnosis of lung cancer a little, and not the specificity is not h

2、igh, the sensitivity is poor. Early diagnosis of lung cancer molecular marker, is solved clinical oncology and medical professionals interested in subject, the early diagnosis of lung cancer is only possible to achieve early treatment can prolong survival time of patients with lung cancer and even i

3、mprove the cure rate. now cyclooxygenase 2 (COX 2, survivin (survivin, vascular endothelial growth factor (VEGF telomerase (telemerase hypoxia inducible factor 1 (HIF 1 ) in lung cancer research progress are summarized below. 1 Survivin (Survivin Lung tissue levels of Survivin expression was signifi

4、cantly higher than adjacent tissues and benign lung tissue 1, Survivin mRNA in lung cancer and metastatic carcinoma increased, indicating that enhanced gene transcription and translation function, and by inhibiting apoptosis, so that the cancer cells immune escape occurs in the development of lung c

5、ancer plays an important role. Nakanishi K 1, using immunohistochemical analysis of 29 cases of atypical adenoid hyperplasia (AAH) and 40 cases of non-bronchioloalveolar carcinoma mucin (nonmucinous BAC, nBAC) Survivin expression, using RT PCR analysis of 63 cases nBAC Survivin mRNA expression, Surv

6、ivin expression was positive rates were: low AAH, 9% (1 / 11), senior AAH, 89% (16/18), nBAC 100%, low-level and AAH AAH and between high-level and senior nBAC significant differences between, Survivin mRNA expression was significantly stronger than in the nBAC normal lung tissue samples. Ikehara M

7、et al 2 on samples of resected lung cancer immune staining, 38 cases of tumor cells Survivin The positive rate of 10% or less, 41 patients with Survivin positive rate of tumor cells> 10%, Survivin positive group was significantly higher in venous invasion opportunity. Survivin-positive patients w

8、as significantly lower than the overall survival rate of patients with Survivin-negative, so inference, Survivin expression in tumor cells patients with lung cancer is a bad prognostic factor. Falleni M et al 3 with quantitative real-time RT-PCR and immunohistochemical determination of 83 cases of N

9、SCLC patients I found that surgical resection specimens, 80 cases (96%) Survivin mRNA levels , squamous cell carcinoma at a high level of Survivin transcription. It was determined 51 Survivin antibodies in serum of lung cancer, 11 patients reacted with purified recombinant Survivin, Survivin antibod

10、y so that the diagnosis of lung cancer, a new marker. Shen C et al 4 study of human lung cancer A549 cells triple structure oligonucleotide (TFO) of anti-Survivin and anti-proliferation genes, by Western blot, cell counting and Annexin V staining and found that Survivin-specific TFO treatment under

11、certain conditions, A549 cells Survivin protein levels decreased significantly, inhibit cell proliferation, induce apoptosis, Survivin as a therapeutic target that will be anti-cancer therapy is expected to become a new strategy. Survivin is highly expressed in tumor tissues, but not expressed in no

12、rmal tissue or low expression , Survivin targeting anti-cancer treatment makes the application possible, but also has better targeting specificity, little effect on normal tissue. In addition, the use of powerful anti-apoptotic activity of Survivin by gene transfer into bone marrow hematopoietic tis

13、sue, the lung cancer chemotherapy on bone marrow hematopoietic function protection, there will be a good prospect. Survivin gene expression decreased with tumor cell differentiation, while an upward trend, indicating a higher invasive lung cancer and poor prognosis. Survivin is highly expressed in l

14、ung cancer, in the normal epithelial Zuzhi low expression or no expression, if a single gene can be fully closed mediated Survivin apoptosis, has good targeting Te Yixing, anti-cancer therapy may be a new way. 2 telomerase (Telemerase Telemerase is an RNA-dependent DNA polymerase, and its activation

15、 can be divided into telomere ends of chromosomes, the cell to avoid the decline and death, and get unlimited proliferative capacity, resulting in tumorigenesis. In recent years, studies have shown that telomerase itself by the telomere RNA component (hTR), telomerase reverse transcriptase (hTERT) a

16、nd telomerase associated protein 1 (TEP1) 3 subunits, of which hTERT is the catalytic subunit of telomerase, the telomerase activity from important role. Liuyun 5 method using the quantitative test of telomerase immunohistochemical staining for quantitative analysis, the results showed that squamous

17、 cell carcinoma and adenocarcinoma of the positive unit of telomerase was no difference in significant lung squamous cell carcinoma and adenocarcinoma of the lung tissue and non-tumor expression of telomerase-positive in real terms the differences were significant. hTERT expression in lung cancer wa

18、s significantly higher than in non-tumor lung tissue. have found that telomerase activity occurs in the early stages of lung cancer, so the quantitative testing and analysis of telomerase may be precancerous lesions and early diagnosis of lung cancer aid diagnosis index of one. telomerase activation

19、 is necessary for cells to immortalized channels, and immortalized tumor progression and is considered a necessary step, and then continue to divide to maintain the tumor, proliferation and survival. for telomere and telomerase in cancer research should further focus on the following aspects: (1) Th

20、e telomere and terminal High grain structure of the enzyme function of its binding proteins, (2) Molecular cloning of telomere and telomerase and related molecular regulatory mechanism of activation, (3) to find specific inhibitors of telomerase and its anti- Tumors, (4) to solve other ways to maint

21、ain telomere - telomere extension via selective (alternative lengthening of telomeres, ALT) interfere with telomerase inhibitors on tumor treatment issues, (5) was raised for the telomere targeted therapy targeting telomerase than for more appropriate treatment. This series of research progress, but

22、 also for lung cancer and anti-cancer drug development to provide new ideas and a good prospect. 3, vascular endothelial growth factor (VEGF The role of VEGF is the strongest known angiogenic factors, can stimulate tumor angiogenesis endothelial cell proliferation, and promote increased permeability

23、 of small veins to induce angiogenesis. Non-small cell lung cancer (NSCLCVEGF of expression and microvessel density ( MVD values were significantly positive correlation between the 6. Some studies indicate that VEGF in NSCLC, the positive rate with age, sex, between histopathology nothing to do with

24、 TNM stage and degree of differentiation, the later stages , the lower the differentiation the higher the positive rate. VEGF in lung cancer invasion and metastasis probably by promoting angiogenesis and by paracrine secretion 7, so the VEGF and its receptor (VEGFR) is considered the most promising

25、anti-angiogenesis target for anti-VEGF therapy provides a theoretical basis. Bevacizumab (a humanized anti-VEGF monoclonal antibody in clinical trials that achieved encouraging efficacy of anti-VEGF therapy has a good prospect. 4 of cyclooxygenase 2 (COX 2 In non-small cell lung cancer (NSCLC) in CO

26、X 2 expression to varying degrees, in particular, well differentiated adenocarcinoma, adenocarcinoma with strong expression of COX 2, while the expression of squamous cell carcinoma is relatively weak. Has been shown that 92% of the adenocarcinoma , 67% of squamous cell carcinoma and large cell carc

27、inoma adenosquamous carcinoma of the expression of both COX 2, small cell lung cancer (SCLC) and normal lung tissue showed no expression of COX 2. In coal preparation, etc. 8 study, COX 2-positive expression rate was 67.2%, slightly lower than the Kim et al 9 The results, also associated with poor p

28、rognosis, COX 2 protein expression in lung cancer microvessel density (MVD was significantly higher than negative expression, indicating that the COX 2 in tumor tissues overexpression and the formation of new blood vessels. It should be noted that in precancerous lesions of lung cancer are also expr

29、essed .71.6% of atypical hyperplasia of bronchial adenocarcinoma samples, 80% of the columnar epithelial hyperplasia were found in the expression of COX 2 10 . Elbayoumy 11 showed that, NNK-induced F344 rat lung adenocarcinoma and squamous cell carcinoma had strong COX 2 expression, suggesting that

30、COX 2 expression and NNK-induced mouse of lung cancer, lung cancer smokers COX 2 expression also significantly enhanced. above studies suggest COX 2 is likely involved in the carcinogenic process of lung cancer and early onset of lung cancer in the work. in tumor formation and growth, the participat

31、ion of biological mechanisms, including foreign metabolism, angiogenesis stimulation, to avoid immune surveillance and suppression of apoptosis 12 14. COX multivariate model COX 2 protein expression and the relationship between survival of patients showed lymph node metastasis, COX 2 protein-positiv

32、e patients with lung cancer independent poor prognostic factors. patients with lung cancer COX 2 protein expression was significantly higher than I stage lung cancer patients, lymph node metastasis in patients with COX 2 protein expression was significantly increased, both indicate that COX 2 in the

33、 development of lung cancer plays an important role in . COX 2 in lung carcinogenesis through a variety of tumor development, metastasis and prognosis play an important role, so the COX 2 inhibitors may become a new target for treatment of lung cancer research. 5 hypoxia-inducible factor 1 (HIF 1 HI

34、F l is the recent discovery of a transcription factor, by and subunits, of which HIF 1 is to determine the activity of hypoxia regulation of HIF 1 subunit, tissue hypoxia when it is played the role of transcription and gene regulation , HIF 1 40 kinds of downstream genes, which, VEGF, TGF and so on

35、play a catalytic role in tumor growth. It has been found in the lung, breast and other tumors overexpressing HIF 1 , and in tumor necrosis and tumor infiltrating the area was the edge, HIF 1 expression was significantly increased, while the stromal cells within the tumor and adjacent normal tissue i

36、s no expression of HIF 1 , indicating that HIF 1 plays in promoting tumor growth important role. necrosis of tumor tissue and tumor tissue expression of HIF 1 over, and no normal lung tissue expression of HIF 1 , and HIF 1 expression and lymph node metastasis and clinical stage are closely related,

37、suggesting that HIF 1 progression and metastasis of lung cancer may be an important factor. HIF 1 and VEGF, MVD were between the expression of certain positive correlation, ie closely related to tumor angiogenesis. studies show that hypoxia signal transduction pathway regulating VEGF in, HIF 1 from

38、the center link and rapid growth of tumor cells caused by hypoxia can induce the expression of HIF 1 , and HIF 1 can also regulate its downstream gene expression of VEGF genes to promote angiogenesis and tumor growth 15. Therefore, HIF 1 could be used as an important indicator of metastatic potentia

39、l of lung cancer can also be used as targets for biological therapy can be achieved by blocking HIF 1 purpose of reduce tumor invasion. lung cancer and many transcription factors involved in the hypoxia inducible factor 1 (HIF 1) is one of them, in which HIF 1a regulation by hypoxia, it is the targe

40、t genes by binding to specific DNA sequences regulating transcription. hypoxic HIF 1 soon in cells stabilized, involved in activation of the maintenance of cell oxygen balance of the various genes such as transcription, such as erythropoietin (EPO), vascular endothelial growth factor (VEGF), so as t

41、o promote angiogenesis and anaerobic glycolysis, the tumor have to adapt to hypoxia. In view of HIF 1 high expression in lung cancer and HIF 1 s central position in oxygen, HIF 1 diagnosis and treatment of lung cancer is expected to provide new ideas. Links to free paper download .com 6 Survivin, Te

42、lemerase, VEGF, COX 2, and the relevance of HIF 1 Experiments show that lung cancer cell line with highly metastatic trials show COX 2 expression and tumor invasion and metastasis ability of a positive correlation, the inhibitor can reduce the transfer. NSCLC with high expression of COX 2 in the ant

43、i-apoptotic features more performance, and often there is a constant expression Survivin 16. use of drugs inhibit the COX 2 gene or the activity of anti-apoptotic activity of cancer cells and the expression of Survivin is lower. Survivin by RNA interference expression closed, COX 2 expression is not

44、 affected. which Survivin inferred COX 2 in the upstream regulation of the expression of Survivin. COX 2 catalyzed prostaglandin E, can stimulate the production of VEGF, thereby promoting tumor angiogenesis 17. selective COX 2 inhibitors can reduce the lung tissue of COX 2 expression and induction o

45、f apoptosis, decreased expression of VEGF protein and hinder the formation and growth of tumor blood vessels, inhibit tumor growth. NSCLC tumor microenvironment in the tumor cells and stromal cells in COX 2 expression is fundamental to increase the expression of VEGF and tumor angiogenesis generatio

46、n, has an important role 18. VEGF also promotes NSCLC Survivin expression in tumor cells 19. It has been reported, VEGF is resistant to tumor necrosis factor and ceramide on endothelial cells induced apoptosis, the use of oligonucleotide closed Survivin, you can eliminate the effect of this resistan

47、ce. On the contrary, in the absence of VEGF oligonucleotide under conditions that can not inhibit endothelial cell viability. NSCLC tissue Survivin, COX 2 and the positive rate of VEGF was positively correlated with each other, the three who coordinated expression. from the anti-apoptosis and angiog

48、enesis of the molecular mechanisms of two ways, Survivin, VEGF are in point of the river. As Telemerase and HIF 1 the relationship between the above, the rapid growth of the tumor caused by hypoxia induced HIF 1 increases, due to Telemerase development of lung cancer also showed high expression of f

49、ive may infer their interactions and common occurrence in the development of NSCLC. currently booming targeted therapy of tumors to induction of apoptosis, inhibition of angiogenesis and COX 2 drugs emerging as a target, and shows a certain effect. Detection of NSCLC, Survivin, Telemerase, VEGF, COX

50、 2, and HIF 1 expression, more user benefit for the targeted treatment options population, predict the treatment effect and a better understanding of the mechanisms of targeted therapy. 7 Outlook Strong sensitivity to identify possible molecular marker highly specific to the diagnosis of lung cancer

51、, so early detection of lung cancer and targeted molecular targeted therapy, prolonged survival time of patients with lung cancer and improve the cure rate of lung cancer direction. References 1 Nakanishi K, Kawai T, Kumaki F, et al. Survivin expression in atypical adenomatous hyperplasia of the lun

52、g J. Am J Clin Pathol, 2003,120 (5): 712 719. 2 Ikehara M, Oshita F, Kameda Y, et al. Expression of Survivin correlated with vessel invasion is a marker of poor prognosis in small adenocarcinoma of the lung J. Oncol Rep, 2002,9 (4): 835 838. 3 Falleni M, Pellegrini C, Marchetti A, et al. Survivin ge

53、ne expression in early stage non small cell lung cancer J Pathol, 2003,200 (5): 620 626. 4 Shen C, Buck A, Polat B, et al. Triplex forming oligodeoxynucleotides targeting Survivin inhibit proliferation and induce apoptosis of human lung carcinoma cells J. Cancer Gene Ther, 2003,10 (5): 403 410. 5 Li

54、u Yun, Chen desire, such as Shen Hong. Squamous carcinoma and adenocarcinoma in situ telomerase reverse transcriptase expression and its pathological significance of quantitative analysis J. Chinese Journal of Stereology and Image Analysis, 2006 , 11 (2:149 151. 6 Gu Yuping, SHU Yong, Chang Wei-Ming

55、. Non-small cell lung cancer COX 2, VEGF and MVD expression and its significance J. Suzhou University (Medical Sciences), 2006,26 (4): 625 628. 7 Padera TP, Kadambi A, Ditomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics J. Science, 2002,296 (5574): 1883 1886. 8

56、 COKING Lu Wang Jian, Fan Jun et al. Lung cancer protein expression and influence on the prognosis of J. Journal of Oncology, 2007,14:1789 1793. 9 Kim HS, Youm HR, lee JS, et al.Correlation between cyclooxygenase 2 and tumor anginogenesis in non small cell lung cancer J. Lung Cancer, 2003,42 (2): 163 170. 10 Husturk S, Kemp B, Kalapurakal SK, et al. Expression of cyclooxygenase 1 and cyclooxygenase 2 in bronchial epithelium and non small cell lung carcinoma J. Cancer, 2002,94 (4):