Tanaka Atsushi, Wang Julia Y, Shia Jinru, Zhou Yihua, Ogawa Makiko, Hendrickson Ronald C, Klimstra David S, Roehrl Michael H A
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Front Oncol. 2020 Jun 10;10:945. doi: 10.3389/fonc.2020.00945. eCollection 2020.
Colorectal cancers are among the most common cancers and a leading cause of cancer death. In our pursuit to discover molecular markers for better characterization and precision theranostics of these cancers, we first conducted global deep proteome analyses and identified maspin (serpin B5, peptidase inhibitor 5) as an upregulated protein in tumor tissue. We then validated its expression in a large cohort of 743 patients with colorectal cancers of all stages and found that both cytoplasmic and nuclear expression varied widely between different patients. Comparison with clinicopathological features revealed that maspin expression levels correlate significantly only with mismatch repair (MMR) status but not with other features. To elucidate the prognostic significance of maspin, we analyzed two outcome-annotated cohorts, one of 572 early stage cancer patients and another of 93 late stage cancer patients. Kaplan-Meier survival, univariate, and multivariate analyses revealed that maspin overexpression predicts longer overall and disease-free survival for early stage microsatellite instability (MSI) subtype colorectal cancer, but there is no correlation with survival for patients with early stage cancer of the microsatellite stability (MSS) subtype or late stage cancer. Our study identifies maspin expression as an independent prognostic marker for risk stratification of early stage MSI subtype colorectal cancer and may provide guidance for improved therapeutic management.
结直肠癌是最常见的癌症之一，也是癌症死亡的主要原因。在我们致力于发现用于更好地表征和精准诊疗这些癌症的分子标志物的过程中，我们首先进行了全蛋白质组深度分析，并确定组织蛋白酶抑制剂（丝氨酸蛋白酶抑制剂B5，肽酶抑制剂5）是肿瘤组织中一种上调的蛋白质。然后，我们在743名各阶段结直肠癌患者的大型队列中验证了其表达情况，发现不同患者之间的细胞质和细胞核表达差异很大。与临床病理特征进行比较后发现，组织蛋白酶抑制剂的表达水平仅与错配修复（MMR）状态显著相关，而与其他特征无关。为了阐明组织蛋白酶抑制剂的预后意义，我们分析了两个带有预后注释的队列，一个队列有572名早期癌症患者，另一个队列有93名晚期癌症患者。Kaplan-Meier生存分析、单因素分析和多因素分析显示，组织蛋白酶抑制剂过表达预示着早期微卫星不稳定（MSI）亚型结直肠癌患者的总生存期和无病生存期更长，但与微卫星稳定（MSS）亚型早期癌症患者或晚期癌症患者的生存期无关。我们的研究确定组织蛋白酶抑制剂表达是早期MSI亚型结直肠癌风险分层的独立预后标志物，并可能为改进治疗管理提供指导。
