The Research Of STK33 Gene And KRAS Gene And EGFR Gene Expression In Lung Cancer

Background:Lung cancer has become the most common malignant tumor with poor prognosis and 10% 5-year survival rate. By histopathology lung cancer was divided into SCLC and NSCLC, and 85% is NSCLC. For NSCLC,surgery is one of the most effective way. However, about 70% of NSCLC patients with newly diagnosed disease has developed to the late and lost opportunities for surgical treatment. So medical treatment become the main treatment for advanced lung cancer, and postoperative adjuvant chemotherapy has been shown to improve survival of patients. But in the past twenty years, increase of NSCLC 3-year and 5-year survival rate does not exceed 4% and the advanced NSCLC 5-year survival rate remain less than 5%. Recently, as the deepening of molecular biology, molecular targeted therapy has become the new hot spot for NSCLC therapy. For advanced NSCLC EGFR-TKIs as the representative of molecular targeted therapy has a very good clinical efficacy. When cancer cells EGFR's exon 18,19 and 21 mutated and activited, the response rate in patients can significantly be increased and overall survival be extended. Patients who are sensitive to gefitinib has EGFR gene mutations because gefitinib was selective to patients. In fact, gefitinib have a significant effect for only a small part of the NSCLC patients, it is invalid for most patients. Studies have shown that the KRAS which encoded EGFR downstream GTPenzyme,whose mutations have been found in up to 30% of lung cancer, KRAS mutations in the RAS inhibited the activity of GTP,which leads to sustained activation of RAS signaling state,thereby causing the cell malignant transformation. It is hard to benefit from adjuvant chemotherapy for Patients with KRAS gene mutations in non-small cell lung cancer,and they are resistant to the EGFR-TKIs. Thus, for non-small cell lung cancer patients we need targeted treatment for KRAS mutations. It is found that in the relevant tumor cell lines which have KRAS gene mutations, suppression of STK33 can lead to synthetic lethal interactions in cancer cells,which has no effect for those cell lines with KRAS wild-type. Further studies indicate that STK33 gene expression was higher in lung cancer than normal lung tissues and benign lesions;STK33 protein expression level in lung,breast and colon cancer is much higher than non-cancerous tissues. However, so far, the biochemical characteristics and biological function of the STK33 is not clear.Objective:To discuss the relationship for STK33 gene expression in lung cancer between EGFR and KRAS mutations and explore the internal-ship between them.We hope to find more molecular biology indicators which correlated to a effective treatment way for EGFR-TKIs to provide more evidences for clinical testing,treament and a better guidandce for individual medicine about the cancer molecular targeted drugs EGFR-TKIs.Methods:In this study, we use real-time PCR method to detect cancer tissue,distal cancer tissue in 70 patients confirmed as lung cancer by pathology and STK33 gene expression in benign lesions from 21 cases while the results and clinical data were analyzed statistically. Further EGFR and KRAS gene were sequenced in 67 patients with NSCLC among those 70 cases with lung cancer, and the results as well as STK33 expression were statistically analyzed.Results:Real-time quantitative PCR results:the expression of STK33 gene in lung cancer tissues (ΔCT=8.87±1.89) is more higher than the expression in distal cancerous tissues (ΔCT=9.41±1.32) and pulmonary benign lesions (ΔCT=9.77±1.35), the differences were statically significant (P<0.05). STK33 expression among NSCLC patients statically show no significance with sex, age, smoking history, tumor size, pathologic type, differentiation, tumor location, stage and lymph node metastasis (P> 0.05).EGFR sequence analysis showed that in NSCLC group lung cancer gene mutation rate was 27%(18/67); two cases with exon 18 2156 G→C,(G719A) and 2155 G→T, (G719C); four cases with K745-A750 missing in exon 19;and 1 case with del2236-2250,E746-A750 and del2236-2253,E746-T751 deletion mutating; one case of insert mutations of 2311-2319, N771-773H and 2302-2310, S768-770D found in exon20,4 cases spot mutation of 2303 G→T,(S768I) and case of 2306 G→T,(V769L),2327 G> A, (R776H) mutation were also found, while in exon 21,3 cases with 2573 T→G (L858R) point mutation,1 case with 2500 G→T, (V834L) point mutation were found.①The expression of STK33 gene in lung cancer tissues is more higher than the expression in distal cancerous tissues and pulmonary benign lesions.②STK33 gene showed no statistical significance in lung cancer with and without EGFR mutations.③Statistical analysis and clinical data showed EGFR mutations have a high incidence among women,no smoking and adenocarcinoma. Age, tumor size, stage, lymph node metastasis and KRAS mutations were not significant.KRAS sequencing showed a 9%(6/67) mutation rate in this group of patients with lung cance which mutations were all decteted in the exonl, of which 4 cases of G12C point mutations,while 2 cases of G12V mutation and they were all heterozygous mutations.①In lung cancer which have KRAS gene mutation STK33 gene showed no statistical significance in lung cancer tissues and distal cancerous tissues and pulmonary benign lesions.②STK33 expression in the lung cancer with and without KRAS mutations showed no statistically significance.③Statistical analysis and clinical data showed KRAS mutations showed no statistically significance in gender,smoking history,pathological type,age,tumor size,stage,lymph node metastasis and EGFR mutations.Conclusions: 1 STK33 gene expression in lung cancer is far higher than the expression in the distal cancerous tissues and benign lesions.2 STK33 gene expression in lung cancer with EGFR mutation is higher than the expression in the distal cancerous tissues and benign lesions.3 STK33 gene expression and KRAS gene mutation in lung cancer show no significant difference in age, gender, smoking history, pathological type, tumor size, stage and lymph node metastasis.4 In women, smoking and adenocarcinoma cancer patients are prone to EGFR mutations, but mutations were not significantly related with age, tumor size, stage and lymph node metastasis.5 STK33 gene were highly expressed in lung cancer tissues with EGFR mutations, but showed no significant difference in those without EGFR mutations.6 STK33 gene expression levels were not related with KRAS gene mutation in lung cancer.7 STK33 gene expression in lung cancer with KRAS mutation is not higher than the expression in distal cancerous tissues and benign lesions.8 EGFR mutations and KRAS mutations occurred respectively in different patients with lung cancer.9 The STK33 gene expression levels between KRAS mutations tissue and wide-type tissue showed no significant difference.10 Analysis of codon 323 sequences in STK33 gene from lung cancer patients reveals no mutations.11 The STK33 gene expression may have a certain contact with the development of lung cancer.