Molecular Profiling of Multiple Human Cancers Defines an Inflammatory Cancer-Associated Molecular Pattern and Uncovers KPNA2 as a Uniform Poor Prognostic Cancer Marker

BackgroundImmune evasion is one of the recognized hallmarks of cancer. Inflammatory responses to cancer can also contribute directly to oncogenesis. Since the immune system is hardwired to protect the host, there is a possibility that cancers, regardless of their histological origins, endow themselves with a common and shared inflammatory cancer-associated molecular pattern (iCAMP) to promote oncoinflammation. However, the definition of iCAMP has not been conceptually and experimentally investigated. Methods and FindingsGenome-wide cDNA expression data was analyzed for 221 normal and 324 cancer specimens from 7 cancer types: breast, prostate, lung, colon, gastric, oral and pancreatic. A total of 96 inflammatory genes with consistent dysregulation were identified, including 44 up-regulated and 52 down-regulated genes. Protein expression was confirmed by immunohistochemistry for some of these genes. The iCAMP contains proteins whose roles in cancer have been implicated and others which are yet to be appreciated. The clinical significance of many iCAMP genes was confirmed in multiple independent cohorts of colon and ovarian cancer patients. In both cases, better prognosis correlated strongly with high CXCL13 and low level of GREM1, LOX, TNFAIP6, CD36, and EDNRA. An “Inflammatory Gene Integrated Score” was further developed from the combination of 18 iCAMP genes in ovarian cancer, which predicted overall survival. Noticeably, as a selective nuclear import protein whose immuno-regulatory function just begins to emerge, karyopherin alpha 2 (KPNA2) is uniformly up-regulated across cancer types. For the first time, the cancer-specific up-regulation of KPNA2 and its clinical significance were verified by tissue microarray analysis in colon and head-neck cancers. ConclusionThis work defines an inflammatory signature shared by seven epithelial cancer types and KPNA2 as a consistently up-regulated protein in cancer. Identification of iCAMP may not only serve as a novel biomarker for prognostication and individualized treatment of cancer, but also have significant biological implications.背景 免疫逃逸是公认的癌症标志性特征之一。针对癌症的炎症反应同样可直接促进肿瘤发生。由于免疫系统的固有功能是保护宿主，因此无论组织学起源如何，癌症均有可能赋予自身一种共通的炎症相关癌症分子模式（inflammatory cancer-associated molecular pattern，iCAMP），以促发肿瘤相关炎症。然而，目前尚未从概念与实验层面开展针对iCAMP的定义研究。 研究方法与结果 本研究对7种癌症类型（乳腺、前列腺、肺、结肠、胃、口腔及胰腺）的221例正常组织样本与324例癌症组织样本的全基因组cDNA表达数据进行了分析。最终共鉴定出96个表达失调趋势一致的炎症相关基因，其中上调基因44个，下调基因52个。部分基因的蛋白表达水平通过免疫组化实验得到了验证。iCAMP包含两类蛋白：一类是已被证实与癌症发生相关的蛋白，另一类则是尚未被认知的蛋白。多项结直肠癌与卵巢癌患者的独立队列研究证实了多数iCAMP基因的临床意义。在两类患者队列中，高表达CXCL13且低表达GREM1、LOX、TNFAIP6、CD36及EDNRA的群体均具有更良好的预后。本研究进一步基于卵巢癌队列中的18个iCAMP基因构建了“炎症基因整合评分（Inflammatory Gene Integrated Score）”，该评分可有效预测患者总生存期。值得注意的是，作为一类选择性核输入蛋白，其免疫调节功能刚刚被揭示的核转运蛋白α2（karyopherin alpha 2, KPNA2）在多种癌症类型中均呈现一致的上调表达。本研究首次通过组织微阵列分析，在结直肠癌与头颈部癌症中验证了KPNA2的癌症特异性上调表达及其临床意义。 结论 本研究明确了7种上皮细胞癌症共有的炎症特征，并证实KPNA2是一类在癌症中持续上调表达的蛋白。iCAMP的鉴定不仅可作为癌症预后评估与个体化治疗的新型生物标志物，同时也具有重要的生物学研究价值。