Liu Qingqing, Stewart John, Wang Hua, Rashid Asif, Zhao Jun, Katz Matthew H, Lee Jeffrey E, Fleming Jason B, Maitra Anirban, Wolff Robert A, Varadhachary Gauri R, Krishnan Sunil, Wang Huamin
Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2017 Feb 10;12(2):e0171985. doi: 10.1371/journal.pone.0171985. eCollection 2017.
Argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme for arginine biosynthesis, is expressed in many types of human malignancies. Recent studies showed that ASS1 may have tumor suppressor function and that ASS1 deficiency is associated with clinical aggressiveness in nasopharyngeal carcinoma, myxofibrosarcomas and bladder cancer. The goal of this study was to evaluate the prognostic impact of ASS1 expression in patients with pancreatic ductal adenocarcinoma (PDAC). Our study included two independent cohorts: untreated cohort, which was comprised of 135 patients with PDAC who underwent pancreatoduodenectomy (PD) without pre-operative neoadjuvant therapy, and treated cohort, which was comprised of 122 patients with PDAC who have completed neoadjuvant therapy and PD. The expression level of ASS1 was evaluated by immunohistochemistry and the results were correlated with clinicopathologic parameters and survival using SPSS statistics. Our study showed that 12% of PDAC in untreated cohort and 15% of PDAC in treated cohort has low expression of ASS1 (ASS1-low). ASS1-low was associated with higher recurrence (p = 0.045), shorter disease-free survival (DFS, 4.8 ± 1.6 months vs 15.3 ± 2.2 months, p = 0.001) and shorter overall survival (OS, 14.6 ± 6.4 months vs 26.5 ± 3.5 months, p = 0.005) in untreated cohort and shorter OS in treated cohort compared to ASS1-high tumors. In multivariate analysis, ASS1-low (HR: 0.45, 95% CI: 0.26-0.79, p = 0.005) was an independent prognostic factor for DFS in untreated cohort and an independent prognostic factor for OS (HR: 0.56, 95% CI: 0.32-0.97, p = 0.04) in treated cohort. Our results provide supporting evidence for future clinical trial using arginine deprivation agents either alone or in combination with conventional chemotherapy in treating pancreatic cancer.
精氨酸琥珀酸合成酶1（ASS1）是精氨酸生物合成的限速酶，在多种人类恶性肿瘤中均有表达。最近的研究表明，ASS1可能具有肿瘤抑制功能，且ASS1缺乏与鼻咽癌、黏液纤维肉瘤和膀胱癌的临床侵袭性相关。本研究的目的是评估ASS1表达对胰腺导管腺癌（PDAC）患者的预后影响。我们的研究包括两个独立队列：未治疗队列，由135例行胰十二指肠切除术（PD）且未接受术前新辅助治疗的PDAC患者组成；治疗队列，由122例完成新辅助治疗及PD的PDAC患者组成。通过免疫组织化学评估ASS1的表达水平，并使用SPSS统计软件将结果与临床病理参数及生存情况进行关联分析。我们的研究显示，未治疗队列中12%的PDAC和治疗队列中15%的PDAC存在ASS1低表达（ASS1-low）。在未治疗队列中，ASS1-low与更高的复发率（p = 0.045）、更短的无病生存期（DFS，4.8±1.6个月对15.3±2.2个月，p = 0.001）和更短的总生存期（OS，14.6±6.4个月对26.5±3.5个月，p = 0.005）相关，与ASS1高表达肿瘤相比，治疗队列中的OS也更短。在多变量分析中，ASS1-low（风险比：0.45，95%置信区间：0.26 - 0.79，p = 0.005）是未治疗队列中DFS的独立预后因素，也是治疗队列中OS的独立预后因素（风险比：0.56，95%置信区间：0.32 - 0.97，p = 0.04）。我们的结果为未来使用精氨酸剥夺剂单独或联合传统化疗治疗胰腺癌的临床试验提供了支持证据。
