Seder Christopher W, Hartojo Wibisono, Lin Lin, Silvers Amy L, Wang Zhuwen, Thomas Dafydd G, Giordano Thomas J, Chen Guoan, Chang Andrew C, Orringer Mark B, Beer David G
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Neoplasia. 2009 Apr;11(4):388-96. doi: 10.1593/neo.81582.
The expression, mechanisms of regulation, and functional impact of INHBA (activin A) in lung adenocarcinoma (AD) have not been fully elucidated.
INHBA expression was examined in 96 lung samples (86 ADs, 10 normal lung) using oligonucleotide microarrays and 187 lung samples (164 ADs, 6 bronchioalveolar carcinomas, and 17 normal lung) using immunohistochemistry. The proliferation of AD cell lines H460 and SKLU1 was examined with WST-1 assays after treatment with recombinant activin A, follistatin, and INHBA-targeting small-interfering RNA. Cells were also treated with 5-aza-2' deoxycytidine and trichostatin A to investigate the role of epigenetic regulation in INHBA expression.
Primary ADs expressed 3.1 times more INHBA mRNA than normal lung. In stage I AD patients, high levels of primary tumor INHBA transcripts were associated with worse prognosis. Immunohistochemistry confirmed higher inhibin betaA protein expression in ADs (78.7%) and bronchioalveolar carcinomas (66.7%) compared with normal lung (11.8%). H460 and SKLU1 demonstrated increased proliferation when treated with exogenous activin A and reduced proliferation when treated with follistatin or INHBA-targeting small-interfering RNA. INHBA mRNA expression in H460 cells was upregulated after treatment with trichostatin A and 5-aza-2' deoxycytidine.
INHBA is overexpressed in AD relative to controls. Inhibin betaA may promote cell proliferation, and its overexpression is associated with worse survival in stage I AD patients. In addition, overexpression of INHBA may be affected by promoter methylation and histone acetylation in a subset of lung ADs.
抑制素βA（激活素A）在肺腺癌（AD）中的表达、调控机制及功能影响尚未完全阐明。
使用寡核苷酸微阵列检测96份肺样本（86例肺腺癌、10例正常肺组织）中抑制素βA的表达，并使用免疫组织化学方法检测187份肺样本（164例肺腺癌、6例细支气管肺泡癌和17例正常肺组织）中抑制素βA的表达。用重组激活素A、卵泡抑素和靶向抑制素βA的小干扰RNA处理肺腺癌细胞系H460和SKLU1后，通过WST-1法检测细胞增殖情况。还用5-氮杂-2'-脱氧胞苷和曲古抑菌素A处理细胞，以研究表观遗传调控在抑制素βA表达中的作用。
原发性肺腺癌中抑制素βA mRNA的表达量是正常肺组织的3.1倍。在I期肺腺癌患者中，原发性肿瘤中高水平的抑制素βA转录本与较差的预后相关。免疫组织化学证实，与正常肺组织（11.8%）相比，肺腺癌（78.7%）和细支气管肺泡癌（66.7%）中抑制素βA蛋白表达更高。用外源性激活素A处理H460和SKLU1细胞后，细胞增殖增加；用卵泡抑素或靶向抑制素βA的小干扰RNA处理后，细胞增殖减少。用曲古抑菌素A和5-氮杂-2'-脱氧胞苷处理H460细胞后，抑制素βA mRNA表达上调。
与对照组相比，抑制素βA在肺腺癌中过表达。抑制素βA可能促进细胞增殖，其过表达与I期肺腺癌患者较差的生存率相关。此外，在一部分肺腺癌中，抑制素βA的过表达可能受启动子甲基化和组蛋白乙酰化的影响。
