Proteomic profiling of lung adenocarcinoma indicates heightened DNA repair, antioxidant mechanisms and identifies LASP1 as a potential negative predictor of survival.
Proteomic profiling of lung adenocarcinoma indicates heightened DNA repair, antioxidant mechanisms and identifies LASP1 as a potential negative predictor of survival.
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DOI：
10.1186/s12014-016-9132-y
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发表时间：
2016
影响因子：
3.8
通讯作者：
Miyamoto S
中科院分区：
文献类型：
--
作者：
Fahrmann JF;Grapov D;Phinney BS;Stroble C;DeFelice BC;Rom W;Gandara DR;Zhang Y;Fiehn O;Pass H;Miyamoto S
肺癌是美国癌症死亡率的主要原因。非小细胞肺癌占所有肺癌的85%，其中腺癌是最常见的组织学类型。肺癌的管理受到由于难以分辨良性和恶性肿瘤而导致的高假阳性率的阻碍。比较恶性和非恶性组织的更好的分子分析将提供有助于肿瘤发生的潜在生物学的重要证据。我们利用蛋白质组学方法分析了38例恶性和非恶性配对组织样本，这些样本来自患有早期（IA/IB期）肺腺癌的当前或既往吸烟者。统计混合效应模型和正交偏最小二乘判别分析被用来识别腺癌蛋白质组中的关键癌症相关扰动。随后针对临床病理学变量评估鉴定的蛋白质。主要的癌症相关蛋白质改变的特征在于：（1）APEX 1、HYOU 1和PDIA 4的升高，表明DNA修复机制增加和抗氧化防御机制增强;（2）LRPPRC、STOML 2、COPG 1和EPRS的增加，表明肿瘤代谢和炎症改变;（3）SPTB、SPTA 1和ANK 1的减少，表明膜完整性失调;（4）SLCA 41降低提示pH调节改变。NSCLC腺癌中HYOU 1、EPRS和LASP 1蛋白水平的增加通过组织微阵列免疫组织化学独立验证。HYOU 1和EPRS的免疫组织化学分别指示用于将组织分类为恶性的AUC为0.952和0.841。LASP 1增加与总生存率差相关（HR 3.66/单位增加; CI 1.37-9.78; p = 0.01）。这些结果揭示了与早期肺腺癌相关的不同蛋白质组学变化，这些变化可能是有用的预后指标和治疗靶点。本文的在线版本（doi：10.1186/s12014-016-9132-y）包含补充材料，可供授权用户使用。
Lung cancer is the leading cause of cancer mortality in the United States. Non-small cell lung cancer accounts for 85% of all lung cancers for which adenocarcinoma is the most common histological type. Management of lung cancer is hindered by high false-positive rates due to difficulty resolving between benign and malignant tumors. Better molecular analysis comparing malignant and non-malignant tissues will provide important evidence of the underlying biology contributing to tumorigenesis. We utilized a proteomics approach to analyze 38 malignant and non-malignant paired tissue samples obtained from current or former smokers with early stage (Stage IA/IB) lung adenocarcinoma. Statistical mixed effects modeling and orthogonal partial least squares discriminant analysis were used to identify key cancer-associated perturbations in the adenocarcinoma proteome. Identified proteins were subsequently assessed against clinicopathological variables. Top cancer-associated protein alterations were characterized by: (1) elevations in APEX1, HYOU1 and PDIA4, indicative of increased DNA repair machinery and heightened anti-oxidant defense mechanisms; (2) increased LRPPRC, STOML2, COPG1 and EPRS, suggesting altered tumor metabolism and inflammation; (3) reductions in SPTB, SPTA1 and ANK1 implying dysregulation of membrane integrity; and (4) decreased SLCA41 suggesting altered pH regulation. Increased protein levels of HYOU1, EPRS and LASP1 in NSCLC adenocarcinoma was independently validated by tissue microarray immunohistochemistry. Immunohistochemistry for HYOU1 and EPRS indicated AUCs of 0.952 and 0.841, respectively, for classifying tissue as malignant. Increased LASP1 correlated with poor overall survival (HR 3.66 per unit increase; CI 1.37–9.78; p = 0.01). These results reveal distinct proteomic changes associated with early stage lung adenocarcinoma that may be useful prognostic indicators and therapeutic targets. The online version of this article (doi:10.1186/s12014-016-9132-y) contains supplementary material, which is available to authorized users.
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影响因子：
14.8
作者：
Keller, Tracy L.;Zocco, Davide;Sundrud, Mark S.;Hendrick, Margaret;Edenius, Maja;Yum, Jinah;Kim, Yeon-Jin;Lee, Hak-Kyo;Cortese, Joseph F.;Wirth, Dyann F.;Dignam, John David;Rao, Anjana;Yeo, Chang-Yeol;Mazitschek, Ralph;Whitman, Malcolm
通讯作者：
Whitman, Malcolm
影响因子：
9.8
作者：
Beller M;Sztalryd C;Southall N;Bell M;Jäckle H;Auld DS;Oliver B
通讯作者：
Oliver B
影响因子：
--
作者：
Orth MF;Cazes A;Butt E;Grunewald TG
通讯作者：
Grunewald TG
影响因子：
16.6
作者：
Liu, Jinfeng;McCleland, Mark;Stawiski, Eric W.;Gnad, Florian;Mayba, Oleg;Haverty, Peter M.;Durinck, Steffen;Chen, Ying-Jiun;Klijn, Christiaan;Jhunjhunwala, Suchit;Lawrence, Michael;Liu, Hanbin;Wan, Yinan;Chopra, Vivek;Yaylaoglu, Murat B.;Yuan, Wenlin;Ha, Connie;Gilbert, Houston N.;Reeder, Jens;Pau, Gregoire;Stinson, Jeremy;Stern, Howard M.;Manning, Gerard;Wu, Thomas D.;Neve, Richard M.;de Sauvage, Frederic J.;Modrusan, Zora;Seshagiri, Somasekar;Firestein, Ron;Zhang, Zemin
通讯作者：
Zhang, Zemin
影响因子：
17.1
作者：
Li XJ;Hayward C;Fong PY;Dominguez M;Hunsucker SW;Lee LW;McLean M;Law S;Butler H;Schirm M;Gingras O;Lamontagne J;Allard R;Chelsky D;Price ND;Lam S;Massion PP;Pass H;Rom WN;Vachani A;Fang KC;Hood L;Kearney P
通讯作者：
Kearney P