Roles Of The Expression Of AKT2,p-AKT In The Pathogenesis Of Non-small-cell Lung Cancer And Expression Correlation Of Them And CyclinD1, MMP-9

Background and ObjectiveThe lung cancer is the most common malignancies in the world, have already become primary death reason of cancer patients in most countries, which severely endangers human health and life. The mechanism of the carcinogenesis of lung tissue is very complex and survival signaling transduction play an important role in it. PI3K/AKT signaling pathway is more important for the carcinogenesis in vivo and considered as primary pathway for cancer cell survive in Western countries, which AKT locates the central position. Suppressing the expression and activation of AKT could block tumoragenesis functions caused not only by itself, but also by many kinds of lung cancer pathogenic relevant gene such as growth factor, Ras, PTEN, etc which locate in up-stream of PI3K/AKT pathway and consequently,could hinder carcinogenesis and development of lung cancer .Recent researches show that activate AKT play an important role in carcinogenesis and development of tumors by modulating priliferation,apoptosis, metastasis,angiogensis and so on.Overexpression and activation of AKT are involved in many kinds of human tumors.But researches concerning the relationship between AKT and tumor are rather rare,no motion to that between AKT and lung cancer in our country. AKT2 is one of three isoforms of AKT.Studies demonsrate amplification , overexpression and activation of AKT2 in human malignancies and AKT2 has been classified as an oncogene. PI3K/AKT2 pathway play an important role in pathogenesis of human cancers. But there is no study about the expression of AKT2 in surgically resected lung carcinoma tissues. Our research employ immunohistochemical method to investigate the expression of AKT2, p-AKT and its target gene products including CyclinDl,MMP-9 as well as the association between them; and to explore the mechanisms in tumorigenesis of lung cancer.Materials and methodsEighty surgically resected non-small-cell lung carcinoma tissues were collected. Among them male 53, female 27; 44 cases were Squamous cancer, 36 cases were adenocarcinoma; In addition, 16 cases were Well-differentiated Squamous cancer, 13 cases were moderately-differentiated Squamous cancer, 15 cases were poorly-differentiated Squamous cancer, 20 cases were Well-differentiated and moderately-differentiated adenocarcinoma, 16 cases were poorly-differentiated adenocarcinoma; and there were lymph nodes metastasis in 44, and no lymph nodes metastasis in 36; 35 cases of benign lung disease were collected as control groups. All the tissues were fixed in 10% neutral formalin and embedded in paraffin. SP immunohistochemical method was performed to detect the expressions of AFG^ p-AKT > CyclinDl and MMP-9. The data were analyzed by software SPSS 10.0, Chi-square Test and exact probability method were used to compare the difference of AKT2, p-AKT, CyclinDl and MMP-9 expression between groups, a =0.05 was considered as the level of tests.Results1. The positive rate of AKT2 in lung cancers (91.3%) was significantly higher than that of AKT2 in benign lung tissues (5.7%) (P<0.05); The positive rate of AKT2 in the group with lymph node metastasis (100.0%) was significantly higher than that of AKT2 in the group without lymph node metastasis (80.6%) (P<0.05); No significant correlation was found between positive AKT2 exprssion and age ,gender, histologic type ,tumor differation and TNM staging (P>0.05).2. The positive rate of p-AKT in lung cancers (78.8%) was significantly higherthan that of p-AKT in benign lung tissues (0.0%)(P<0.05); The positive rate of p-AKT in Well-differentiated and moderately-differentiated adenocarcinoma (95.0%) was significantly higher than that of p-AKT in poorly-differentiated adenocarcinoma (50.0%)(P<0.05).In the group with and without lymph node metastasis , The positive rate were 84.1% and 72.2% respectively, the difference between them was not significant (P>0.05). The positive rate of p-AKT in stage I — II lung cancers and stage III-IV lung cancers were 78.0% and 81.0% respectively, the difference between them was not significant (P>0.05). No significant correlation was found between positive p-AKT expression and age, gender, histologic type and Squamous cancer differation (P>0.05).3. The positive rate of CyclinDl in lung cancers (76.3%) was significantly higher than that of CyclinDl in benign lung tissues (0.0%)(P<0.05); The positive rate of CyclinDl in the group with lymph node metastasis (86.4%) was significantly higher than that of CyclinDl in in the group without lymph node metastasis (63.9%) (F<0.05); The positive rate of CyclinDl in poorly-differentiated Squamous cancer (93.3%) was significantly higher than that of CyclinDl in Well-differentiated Squamous cancer (50%)(P<0.05).No significant correlation was found between positive CyclinDl expression and age, gender, histologic type , adenocarcinoma differation , TNM staging (P>0.05).4. The positive rate of MMP-9 in lung cancers (72.5%) was significantly higher than that of CyclinDl in benign lung tissues (11.4%)(P<0.05); The positive rate of MMP-9 in the group with lymph node metastasis (84.1%) was significantly higher than that of MMP-9 in the group without lymph node metastasis (58.3%) (P<0.05); The positive rate of MMP-9 in stage III-IV lung cancers (90.5%) was significantly higher than that of MMP-9 in stage I-II lung cancers (66.1%) (P<0.05); The positive rate of MMP-9 in poorly-differentiated Squamous cancer (93.3%) was significantly higher than that of MMP-9 in Well-differentiated Squamous cancer (43.8%)(P<0.05).No significant correlation was found between positive MMP-9 expression and age, gender, histologic type , adenocarcinoma differation (P>0.05).5. Positive correlations were observed between the expression of AKT2 andCyclinDl, MMP-9 in lung cancers(P<0.05).6. Positive correlations were observed between the expression of p-AKT and CyclinDl in lung cancers(P<0.05). No correlations were observed between the expression of p-AKT and MMP-9 in lung cancers(P>0.05).7. Positive correlations were observed between the expression of AKT2 and p-AKT in lung cancers(P<0.05).Conclusion1. The high positive rate of AKT2 and p-AKT in lung cancer and positive correlations between AKT2 and p-AKT indicate AKT activation may be present in lung cancers and AKT2 may be the predominant isoform of AKT involved in carcinogenesis and development of lung cancer. The expression of AKT2 is closely related to lymph node metastasis, and it could be used to evaluate prognosis.2. CyclinDl only express in the cancer tissues, not in benign lung tissues. The expression of CyclinDl is closely related to lymph node metastasis. CyclinDl may participate in lung carcinogenesis and development of lung cancer. Both p-AKT and AKT2 expression are positively related to CyclinDl in lung cancer indicate that the high positive rate of CyclinDl may correlate to activation of AKT. the high positive rate of CyclinDl could be used to evaluate prognosis.3. The positive rate of MMP-9 in lung cancers is significantly higher than that of MMP-9 in benign lung tissues. The expression of MMP-9 is closely related to lymph node metastasis and TNM stages. The expression of MMP-9 may help to judge the degree of malignant behavior and could be used to evaluate prognosis. There is no relationship between p-AKT and MMP-9 suggests that MMP-9 may participate in carcinogenesis and development of lung cancer through other routes.4. PI3K/AKT signaling pathway is activated in lung cancer tissues and may play an important role in the tumorigenesis of lung cancer.