1 Characteristics of PCNA PCNA is a protein with a molecular weight of 36KD. It is synthesized in the nucleus and exists in the nucleus. It is an auxiliary protein of DNA polymerase delta. There are both soluble and insoluble PCNAs in the nucleus. Soluble PCNA is expressed in all stages of the cell cycle, and its amount does not change significantly during DNA synthesis. It is easily extracted by detergents and destroyed by methanol; insoluble PCNA is relatively stable. It is not easy to be eluted by detergent and destroyed by methanol. This kind of PCNA has no obvious expression in G0 ～ G1 phase cells. In the late stage of G1, its expression increases greatly, S phase reaches the peak, G2 ～ M phase decreases obviously, and its quantity changes Consistent with DNA synthesis, detection of its expression in cells can be used as an indicator to evaluate cell proliferation status [1,2,4].
2 The study of PCNA in tumors Tumor cells have strong proliferative activity, and PCNA can be used as an indicator to evaluate the proliferation status of cells. Therefore, PCNA has been studied in many tumors at home and abroad, involving PCNA and tumor development [5,6], grade [1,7 ～ 10], staging [1,10], radiotherapy sensitivity [11,12] , Prognosis [1,7,8,10,13-20], recurrence and metastasis [1,21], cause of death [20], tumor markers [18,22] and other aspects of correlation, many Conclusions, but in some respects, there are still some controversies due to the difference between the author and the tumor being studied. Even if there are no controversial conclusions, they are derived from one or several tumors. Whether these conclusions apply to all tumors is still To be further studied.
3 PCNA research in lung cancer PCNA research in lung cancer is also more, many authors are devoted to this aspect of the discussion, hoping to find meaningful and valuable results, but until now, some results of PCNA research in lung cancer There is also controversy [23].
3.1 The relationship between PCNA and the development of lung cancer Xia Shuyue et al. [6] found that the expression of PCNA gradually increased and the number of positive cells gradually increased during the study of the occurrence and development of lung squamous cell carcinoma. In mild, moderate and severe dysplasia, carcinoma in situ and invasive carcinoma, the PCNA marker index was 12.5 ± 8.7, 43.3 ± 14.9, 68.1 ± 9.1, 74.6 ± 8.2, 65.4 ± 23.6, and normal and mild, moderate Compared with dysplastic epithelium, the PCNA marker index of infiltrating carcinoma, carcinoma in situ, and severe dysplasia was significantly increased, and the number of PCNA positive cells was also significantly increased. It is believed that PCNA expression is a sign of abnormal cell proliferation and can be used as a reference index for the early diagnosis of lung squamous cell carcinoma. But this is only a preliminary exploration in lung squamous cell carcinoma, and the number of cases is small. Whether it can be used as a reference index for early diagnosis of lung squamous cell carcinoma needs further verification.
3.2 The relationship between PCNA and lung cancer type. The author [15,24] believes that PCNA is expressed differently in different types of lung cancer. The average squamous cell carcinoma PCNA marker index is about 52%, adenocarcinoma is 49%, large cell lung cancer is 76%, small Cell lung cancer is 63%. The results of He Jie et al. [25] were: lung squamous cell carcinoma marker index was 0.51 ± 0.23, and adenocarcinoma was 0.69 ± 0.34. The expression is also different between different subtypes of the same type. Wang Enhua et al [13] analyzed each subtype in 86 cases of lung adenocarcinoma: PCNA expression in bronchioloalveolar carcinoma is about 0.22 ± 0.17, in alveolar adenocarcinoma is about 0.36 ± 0.12, in large cell carcinoma is about It is 0.67 ± 0.10. However, some authors believe that the expression of PCNA can only reflect the proliferation status of cells, regardless of the type of histology. Castellano [26], Fontanini [14], Fujii [27], etc. support this view.
3.3 The relationship between PCNA and the degree of lung cancer differentiation. Studies have shown that the expression of PCNA decreases as the degree of lung cancer differentiation increases. In the study of lung adenocarcinoma, Wang Enhua [13] found that the highest differentiated group had the lowest PCNA marker index of about 0.19 ± 0.10, the middle differentiated group was slightly higher, about 0.35 ± 0.10, and the poorly differentiated group had the highest value, about 0.55 ± 0.17; He Jie et al. [25] analyzed the expression of PCNA in lung squamous cell carcinoma and lung adenocarcinoma, and found that the PCNA marker index was positively correlated with tumor grade. Zhao et al. [28] reached the same conclusion in 73 cases of lung cancer. It can be seen that the expression of PCNA in lung cancer can reflect the differentiation of lung cancer cells, which indicates the degree of tumor malignancy. This is basically consistent with the findings in many other tumors.
3.4 The relationship between PCNA and lung cancer stage Most studies have shown that the expression of PCNA is related to the stage of lung cancer. The later the stage, the higher the expression of PCNA. Ishida et al. [29] in the 211 cases of non-small cell lung cancer statistically calculated the average expression of PCNA in stages â… , â…¡, â…¢a and â…¢b of 30%, 24%, 40% and 50% respectively, with a gradually increasing trend, but Phase â… and â…¡ have little difference. The research by Wang Enhua et al. [13] also believes that the expression of PCNA in lung cancer is related to N stage and M stage. As the stage increases, the expression of PCNA increases. However, some authors hold the opposite opinion. In the study of peripheral non-small cell lung cancer, Fontanini et al. [14] found that the expression of PCNA has nothing to do with the stage. Their results are: the average expression of PCNA in T1 is about 18%, and that in T2 is about 10%. Whether the expression of PCNA is suppressed by the host immune system in the early (â… , â…¡) lung cancer, the change is not obvious, and the expression of the advanced lung cancer is significantly increased due to the weakened immune suppression, which remains to be discussed.
3.5 Relationship between PCNA and vascular invasion of lung cancer Fontanini et al. [14] found in 40 cases of peripheral, lymph node-negative non-small cell lung cancer (NSCLC) that the expression of PCNA was significantly related to vascular invasion, and there was PCNA in the vascular invasion group The expression was significantly higher than the non-vascular invasion group, with an average of 40% and 10%, respectively. Fujii et al. [27] also found that the expression of PCNA is significantly associated with lung cancer vascular invasion. This may be related to those with high expression of PCNA, poor differentiation, high malignancy, and easy erosion of blood vessels.
3.6 Relationship between PCNA and prognosis of lung cancer Some authors believe that the lower the expression of PCNA, the longer the survival time and the better the prognosis. Wang Enhua et al [13] analyzed 86 cases of lung adenocarcinoma that were surgically removed and found that there were significant differences in the expression of PCNA between the group survived within 3 years and the group with more than 5 years. ± 0.15; Ishida et al. [29] also found in stage I NSCLC that in the 5-year survival group, the survival rate of the PCNA (+) group was significantly lower than the PCNA (-) group; Fujii et al. [26] also supported this View. However, a considerable number of authors believe that PCNA alone cannot evaluate the prognosis of NSCLC. Matturri [30], Monraval [31], Castellano [26], Ebina [32], etc. studied the expression of PCNA and the survival time of NSCLC after surgery. Relationship, did not find a clear correlation. Consider that this is because the prognosis of lung cancer is determined by a variety of factors: such as pathological type, pathological stage, differentiation, treatment status, comorbidities, age, physical condition, and expression of PCNA. It is difficult to rely on PCNA alone. Predict the prognosis of lung cancer.
3.7 The relationship between PCNA and lung cancer recurrence Ogawa et al [33] found in 35 patients with stage â… NSCLC recurrence after surgery that the recurrence time of PCNA (+) group was significantly shorter than that of PCNA (-) group, and the median tumor-free survival time was 2.5 Years and 4 years, it is believed that PCNA can predict the length of relapse time after stage â… NSCLC. However, there are too few cases studied and the scope is narrow, and the results need to be confirmed.
3.8 Correlation between PCNA and other markers of lung cancer Fontanini et al [14] found that the expression of PCNA in peripheral lung cancer was significantly higher than that of DNA euploid in DNA aneuploidy, and was significantly related to the DNAS stage score of aneuploidy, PCNA expression A high split index is higher than that with low PCNA expression. Other studies [13,15,24,28,29,34] have shown that the expression of PCNA in lung cancer is related to cell composition, DNA index, AgNORs count, Ki67 and so on. These are mostly the first reports. I wonder if the results can be repeated. If the conclusions can be confirmed, the application and research of PCNA will be more extensive in clinical and basic research.
It can be seen from the above that the study of PCNA in lung cancer has penetrated into all aspects of lung cancer, but the results obtained in many aspects are not uniform, and there are many reasons for this inconsistent result. The preliminary analysis includes the following factors: 1) Factors of the tumor itself: There are large differences in cell proliferation between tumors and tumors and between different parts of the same tumor [26,36,37], resulting in uneven expression of PCNA. 2) Effect of sampling: Due to the uneven expression of PCNA between different parts of the tumor, the high expression area may be obtained when the material is taken, or the medium expression area or the low expression area may be taken, so that the counting result cannot represent the entire tumor. 3) Influencing factors in the production process: the concentration of formalin when the tissue is fixed, the length of the fixed time, the temperature of the baked slice and the duration of the baked slice have an effect on the antigenicity of PCNA. If the concentration of the fixing solution is too high, the fixing time is too long, the temperature of the baking sheet is too high, and the baking sheet time is too long, it will reduce the antigenicity of PCNA and cause the antigenicity to disappear [1,2]. 4) Influencing factors in the process of immunohistochemical staining: different antibodies used in the process of immunohistochemical staining result in different PCNA results; microwave oven heating can restore the antigenicity of PCNA and enhance the immunohistochemical staining effect of slices [37], use microwave oven Processing slices can increase the detection value; in addition, antibody titers, endogenous peroxidase blocking conditions, DAB color development time, background depth of hematoxylin staining, etc. will affect the effect of the stained film, resulting in false negative or False positives make the test results change. 5) The impact of the result judgment: due to the different negative positive staining standards set by each person, the selected field of view is different, and the total number of counted cells is different, which also causes a certain human deviation.
Due to the above many influencing factors in the experiment, it is difficult to compare the results of different authors in lung cancer or in different tumors. Therefore, it is necessary to adopt uniform standards for PCNA immunohistochemistry research. Reduce experimental errors and human bias, so that the results of each other are comparable.
In short, no matter in terms of the entire tumor or lung cancer alone, there are many studies on PCNA, and many results have been obtained with clinical value. However, due to the variability of the tumor itself and the differences in people ’s research methods, There is some controversy in the results obtained, which needs to be further verified so that a consistent conclusion can be reached and applied to the clinic to guide clinical practice.
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