Overexpression of inhibin βA and SPARC in pancreatic cancer patients with shorter disease free interval and survival

Abstract

[한글]

Inhibin βA는 serine/threonine 활성효소 기능을 가지는 세포막간 수용체에 결합하는 다기능의 싸이토카인으로 구성된 TGF-β superfamily에 속하며 췌장암에서 발현이 증가된다. SPARC(Secreted protein acidic and rich in cysteine)는 내피세포에 의해 분비되는 당단백질로 췌장암에서 흔한 비정상 메틸화의 대상이 된다. 저자 등은 췌장암 조직에서 cDNA microarray를 이용하여 Inhibin βA와 SPARC의 유전자 발현을 확인하였고 조직미세배열기술(Tissue microarray; TMA)과 면역화학염색법을 이용하여 Inhibin βA와 SPARC의 유전자의 단백질 발현을 확인하고 Inhibin βA와 SPARC의 발현이 췌장암 환자의 생존과 재발을 예측할 수 있는지 알아보고자 하였다.수술을 시행한 췌장암 환자 39명의 임상적 특징, 재발과 생존기간에 대해 조사하였다. 췌장암 환자의 조직에서부터 TMA을 제작하였고 항inhibin βA항체와 항SPARC항체를 사용하여 면역화학염색을 시행하여 inhibin βA와 SPARC의 단백질 발현을 확인하였고 임상적 특징과의 상관관계를 분석하여 다음과 같은 결과를 얻었다.39명의 환자 중 28명은 남자, 11명은 여자였고 평균연령은 60.6± 8.4세였다. 췌장암의 위치는 두부가 26예(66.7%), 췌부가 2예(5.1%), 미부가 11예(28.2%)였고 췌장암의 병리학적 병기는 1기가 3예(7.7%), 2기가 18예(46.2%), 3기가 10예(25.6%), 4기가 8예(20.5%)였다.39명의 환자 중 32명(82%)에서 inhibin βA 양성이었으며 inhibin βA의 발현과 나이, 성별, T병기, N병기, M병기, TNM병기는 유의한 상관관계가 없었다. 39명의 환자 중 23명(59%)에서 SPARC양성이었으며 SPARC의 발현과 나이, 성별, T병기, N병기, M병기, TNM병기는 유의한 상관관계가 없었다. inhibin βA와 SPARC의 발현과 췌장암 환자의 생존기간과 재발기간과의 유의한 상관관계는 나타나지 않았으나 inhibin βA와 SPARC이 발현이 나타난 환자에서 inhibin βA와 SPARC이 발현이 환자에 비해 췌장암 환자의 생존기간과 재발기간이 좀 더 긴 경향을 보였다.이상의 결과를 종합하면 본 연구에서 췌장암환자에서 inhibin βA와 SPARC발현이 증가함을 확인하였고 inhibin βA와 SPARC가 췌장암 환자에서 생존과 재발을 예측할 수 있는 예후인자로서의 가능성을 추측할 수 있으며 추가적인 연구를 통해 이를 증명하는 것이 필요할 것으로 판단된다.

[영문]

Inhibins βA belong to the transforming growth factor-β(TGF-β) superfamily of multifunctional cytokines that bind to transmembrane receptors with serine/threonine kinase activity. SPARC(Secreted protein acidic and rich in cysteine) is a phosphorylated, acidic, glycine-rich glycoprotein of 43 kDa that is secreted by endothelial cells. We characterized up-regulation of inhibin βA and SPARC using cDNA microarray originating from human pancreatic tissues. We aimed to validate expression of inhibin βA and SPRAC using immunohistochemistry with tissue microarray and evaluate that inhibin βA and SPARC can predict for survival and disease free interval (DFI) of patients with pancreatic cancer. Thirty nine patients who have underwent pancreatic cancer surgery included and clinical characteristics, recurrence and duration of survival were analyzed. We used tissue microarrays out of pancreatic cancer tissues resected from patients. Immunohistochemical stain with anti-inhibin βA-antibody and anti-SPARC-antibody would be used for validate the expression of inhibin βA and SPARC. The stains were reviewed by two pathologists blind to the original diagnosis and stained cells were scored semiquantitatively as negative, focal positive, diffuse positive, (0-2) using a previously published method (Human pathol 2004;35:357-366). DFI and survival were calculated with the Kaplan-Meier method and their differences were evaluated by the log rank test. Of the 39 patients (28 men, 11 women; mean age 60.6 [8.4] years), stage(TNM staging) I was 3, stage II was 18, stage III was 10, and stage IV was 8, respectively. Immunohistochemical stain for inhibin βA was diffuse positive in 21 patients, focal positive in 12 patients and negative in 6 patients. Immunohistochemical stain for SPARC was diffuse positive in 9 patients, focal positive in 14 patients and negative in 16 patients. Patients with inhibin βA overexpression (diffuse positive) tended to be shorter duration of DFI than without inhibin βA overexpression (median 6 months vs 10 months, p=NS) and trended toward shorter survival (median 14 months vs 23 months) although this did not reach significance. Patients with SPARC overexpression tended to be shorter duration of DFI than without SPARC overexpression (median 7 months vs 9 months, p=NS) and trended toward shorter survival (median 10 months vs 19 months) although this did not reach significance. These data show inhibin βA and SPARC was overexpressed in patients with pancreatic ductal adenocarcinoma and suggest inhibin βA and SPARC overexpression tend to be correlated with DFI and survival.