engleski

The expression pattern of key molecules of wnt signaling pathway in brain metastases from lung cancer

We analyzed Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1), the key players in the classical Wnt signaling pathway in brain metastases that originated from primary lung carcinomas. Protein expressions and localizations were analyzed by immunohistochemistry. Genetic changes of E-cadherin were tested by PCR/loss of heterozygosity (LOH) method using D16S752, D16S265 and D16S398 microsatellite markers for CDH1 gene. Heteroduplex method was used to investigate potential mutations in beta-catenin. The results showed 36% of samples with LOH of the CDH1 gene. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and SCLC were significantly associated to E-cadherin genetic changes with c2= 10.364 ; df=1 ; P=0.001. A type of genomic instability - MSI was also detected in one metastasis from adenocarcinoma. The results on protein expressions of DVL1 and DVL3 showed overexpression in brain metastasis tissues in 87.1 % and 90.3% of samples respectively. Nuclear staining of the proteins was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. Overall 80% of samples had downregulation of E-cadherin expression. Beta-catenin, was upregulated in 56%, and transferred to the nucleus in 36% of metastases. Approximately 25% of metastases showed simultaneous nuclear localization of dishevelled and beta-catenin. When DVL1 and DVL3 were upregulated the number of cases with nuclear beta-catenin significantly increased (P=0.0001). Our findings on changes of the wnt molecular components may contribute to better understanding of human brain metastases genetic profiles. Elucidating pathophysiological mechanisms conditioning lung cancer metastasis to the brain could offer new prognostic markers for specific tumor type.

wnt signaling pathway; brain metastases; DVL1; DVL3; CDH1; CTNNB1

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