High Co-expression of Large Tenascin C Splice Variants in Stromal Tissue and Annexin A2 in Cancer Cell Membranes is Associated with Poor Prognosis in Pancreatic Cancer
High Co-expression of Large Tenascin C Splice Variants in Stromal Tissue and Annexin A2 in Cancer Cell Membranes is Associated with Poor Prognosis in Pancreatic Cancer
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DOI：
10.1245/s10434-019-07708-x
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发表时间：
2020-03-01
影响因子：
3.7
通讯作者：
Shirabe, Ken
中科院分区：
文献类型：
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作者：
Hagiwara, Kei;Harimoto, Norifumi;Shirabe, Ken
背景胰腺癌组织中含有丰富的间质成分，包括细胞外基质蛋白，如TnC(TnC)，它以大剪接(TNC-L)和非大剪接变异体的形式存在。在这里，我们检测了人胰腺癌标本中总TNC(TNC-ALL)和TNC-L在间质以及TNC的细胞表面受体Annexin A2(ANXA2)中的表达，并评价了它们作为胰腺癌预后标志物的意义。方法检测106例胰腺癌组织中ANXA2、TNC-ALL和TNC-L的表达。免疫组织化学方法检测蛋白表达，并进行半定量评分。用COX比例风险分析评价蛋白表达与临床病理因素和预后的关系。结果TNC-ALL和TNC-L主要在癌细胞间质中表达，而ANXA2主要在癌细胞膜上表达。TNC-ALL在非肿瘤胰腺组织中也有表达。高水平的间质TNC-L和膜性ANXA2，而不是间质TNC-ALL，独立地与癌症进展和不良预后相关。此外，与TNC-ALL、TNC-L或ANXA2单独检测相比，TNC-L和膜型ANXA2的高共同表达是预后不良的一个更好的指标。结论与单独检测TNC-L或ANXA2相比，间质TNC-L和膜型ANXA2共同表达是胰腺癌患者较差的预后指标。此外，靶向间质TNC和癌细胞ANXA2之间的串扰可能是克服难治性胰腺癌的一种有前途的治疗策略。
Background Pancreatic cancer tissue contains abundant stromal components, including extracellular matrix proteins such as tenascin C (TNC), which exists as large (TNC-L) and non-large splice variants. Here, we examined human pancreatic cancer specimens for the expression of total TNC (TNC-ALL) and TNC-L in the stroma and annexin A2 (ANXA2), a cell surface receptor for TNC, and evaluated their significance as prognostic markers for pancreatic cancer. Methods Expression of ANXA2, TNC-ALL, and TNC-L was examined in 106 pancreatic cancer tissues from patients who underwent curative resection and who had not received prior therapy or surgery. Protein expression was measured by immunohistochemistry and scored on a semi-quantitative scale. The relationships between protein expression, clinicopathological factors, and prognosis were evaluated by Cox proportional hazards analysis. Results TNC-ALL and TNC-L were detected mainly in the stroma, whereas ANXA2 was predominantly expressed in cancer cell membranes. TNC-ALL was also expressed in non-tumor pancreatic tissue. High levels of stromal TNC-L and membranous ANXA2, but not stromal TNC-ALL, were independently associated with cancer progression and poor prognosis. Moreover, high co-expression of stromal TNC-L and membranous ANXA2 was a superior indicator of poor prognosis compared with detection of TNC-ALL, TNC-L, or ANXA2 alone. Conclusions Our data suggest that co-expression of stromal TNC-L and membranous ANXA2 is a poor prognostic marker compared with detection of TNC-L or ANXA2 alone for pancreatic cancer patients. Additionally, targeting of crosstalk between stromal TNC and cancer cell ANXA2 could be a promising therapeutic strategy to overcome refractory pancreatic cancer.