| BackgroundAbnormal inhibition has become one of the focuses in the carcinoma field. Abnormal inhibition of physiological apoptosis is thought to be a critical step for carcinogenesis or tumorigenesis. In addition to the Bcl-2 protein family, which includes anti-apoptotic and pro-apoptotic factors, the inhibitor of apoptosis protein (IAP), a relative new protein family, is mainly involved in anti-apoptosis. Survivin, a unique member in the IAP family, is regulated by cell cycle, and involved in both control of programmed cell death (apoptosis) and regulation of cell division. Survivin is undetectable in most normal adult tissues but is highly expressed in cancer, which is a promising tumor specific biomarker.Small cell carcinomas are uncommon malignant tumors with poor survival and aggressive behavior. The majority of small cell carcinoma occurs in the lung. Extra-pulmonary small cell carcinoma includes mostly primary esophagus small cell carcinoma. Some researchers think the morphological and immunohistochemical patterns of this tumor are similar to its pulmonary counterpart. But other researchers think that PESC is a clinicopathologic entity distinct from SCLC. Moreover, there are two viewpoints on the histological origin of PESC at present. One is that PESC originates from neuroendocrine cells of the submucosal gland or stratum basal, i.e. the amine precursor uptake and decarboxylation cells (APUD) confirmed histologically. The other is that PESC originates from multipotential stem cells of the endoderm. Most of these cells may be differentiated into squamous cell carcinoma and some differentiated into adenocarcinoma or small cell carcinoma.There is no agreement on the therapy of PESC due to its lower incidence rate and limited knowledge on the disease, so the prognosis of PESC is poor.The molecular mechanism of carcinogenesis has been extensively explored in non small cell lung. But the research progress of clinical and pathogenic mechanism in SCLC and PESC is very slow, especially in PESC.At present, the underlying carcinogenesis mechanisms of SCLC and PESC are not fully understood. But the researchers on tumorigenesis have suggested that abnormal inhibition of apoptosis be a critical step for carcinogenesis of other tumors. So we explore the mechanisms of anti-apoptosis in SCLC and PESC from the two aspects below.Part One:Objective To investigate the difference of the expression of several apoptosis genes and the pathogenic mechanism between SCLC and PESC. That could provide the clues to understand the difference of carcinogenesis mechanisms between SCLC and PESC.Methods The expressions of Survivin, Bcl-2, MTp53, Caspase-3, Ki-67 protein in 41 primary SCLC were analyzed immunohistochemically. The results compared with the previous results of PESC which had been achieved by our research group. Results1. There were not significant differences in rates of expression of Survivin, Bcl-2, MTp53, Caspase-3, Ki-67 between SCLC and PESC (P<0.05).2. In SCLC, the expression of Caspase-3 in the Survivin negative group (62.1%, 18/29) was significantly higher than that of the Survivin positive group (25%, 3/12), and there was negative correlation between the expression of Caspase-3 and Survivin (r=-0.337,P< 0.05). In PESC, the expression of Caspase-3 in the Survivin negative group (72.4%, 21/29) was significantly higher than that of the Survivin positive group (30.0%, 3/10), and there was negative correlation between the expression of Caspase-3 and Survivin (r=-0.381, P< 0.05). In SCLC and PESC, there was no relationships between the expression of Caspase-3 and that of Bcl-2(P>0.05).3. In SCLC, the expression of MTP53 in the Bcl-2 positive group (69.2%, 18/26) was significantly higher than that of the Bcl-2 negative group (33.3%, 5/15), and there was positive correlation between the expression of MTP3 and Bcl-2(r=0.348, P< 0.05). In PESC, the expression of MTP53 in the Bcl-2 positive group (73.7%, 14/19) was significantly higher than that of the Bcl-2 negative group (35.0%, 7/20), and there was positive correlation between the expression of MTP3 and Bcl-2(r=0.388, P< 0.05). In SCLC and PESC, there was no relationship between the expression of Survivin and that of MTP53(P>0.05).4. In SCLC and PESC, there was no relationship between the expression of Survivin and that of Bcl-2(P >0.05).Conclusion There are several similar points in anti-apoptosis pathway between SCLC and PESC: Survivin, Bcl-2 and MTP53 are involved in SCLC and PESC oncogenesis and progression. These proteins may play the similar roles in carcinogenesis between SCLC and PESC.Part Two:Objective To investigate the difference of the expression of several apoptosis genes and the pathogenic mechanism between SCLC and NSCLC.Methods The expression of Survivin, Bcl-2, MTp53, Caspase-3, Ki-67 proteins in 30 primary NSCLC were analyzed immunohistochemically. The expression of Survivin, Bcl-2, MTp53, Caspase-3, Ki-67 between SCLC and NSCLC were compared, the relationship among them and clinical data were analyzed.Results1. The percentage (63.4%) that patients' age was smaller than 60 in SCLC is higher than that of NSCLC (36.7%) (P<0.05). The percentage of III-IV stage in SCLC was higher than that of NSCLC. There were no difference in gender and lymph node metastasis between SCLC and NSCLC. 2. The expression of Survivin, Bcl-2 in SCLC and NSCLC had significant differences compared with the control group (P<0.01); the expression of Survivin in SCLC(29.3%) was significantly lower than that of NSCLC(70%)(P<0.01); the expression of Bcl-2 in SCLC(63.4%)was significantly higher than that of NSCLC(30%)(P<0.01); there were not significant differences in expression of Caspase-3 between SCLC and NSCLC(P>0.05).3. The Ki-67 Index in SCLC and NSCLC had significant differences compared with the control group (P<0.01). The Ki-67 Index in SCLC (11.12±0.37%) was higher than that of NSCLC (4.55±0.28%) (P<0.01).4. In SCLC, there was negative correlation between the expression of Caspase-3 and Survivin (r=-0.337, P< 0.05); in NSCLC, the expression of Caspase-3 in the Survivin positive group(19.0% ,4/21) was significantly lower than that of the Survivin negative group(88.9%,8/9), and there was negative correlation between the expression of Caspase-3 and Survivin (r=-0.653, P< 0.01). In SCLC, there was positive correlation between the expression of MTP3 and Bcl-2(r=0.348, P<0.05), but there was no correlation in NSCLC. In SCLC and NSCLC, there were no relationships between the expression of Survivin and that of BcI-2(P>0.05).5. In SCLC, the KI of Caspase-3 positive group was 18.16±0.29%,while 6.62±0.40% for the Caspase-3 negative group, significant difference was found between the two groups(P<0.05); in NSCLC, there were no relationships between the expressions of several apoptosis genes and age,gender,lymph node metastasis and clinical stage(P >0.05).6. In SCLC, there was significant difference in lymph node metastasis rate between the positive and negative group of Survivin (P<0.05).Conclusion Survivin, Bcl-2 and MTP53 are involved in SCLC and NSCLC oncogenesis and progression. Survivin gene may be an auxiliary factor in SCLC apoptosis regulation by inhibition of activity of Caspase-3, and Bcl-2 may play an important role in SCLC oncogenesis and progression. Survivin is an important factor and Bcl-2 is an auxiliary one in NSCLC anti-apoptosis regulation. The difference of the expression of Survivin and Bcl-2 is one of the important differences in the pathogenic mechanism between SCLC and NSCLC, from which we should study the different treatment strategy of SCLC and NSCLC.
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