HYAL-1-induced autophagy facilitates pancreatic fistula for patients who underwent pancreaticoduodenectomy
HYAL-1-induced autophagy facilitates pancreatic fistula for patients who underwent pancreaticoduodenectomy
复制标题
HYAL-1-诱导的自噬促进接受胰十二指肠切除术的患者发生胰瘘
DOI：
10.1096/fj.201901583r
复制
发表时间：
2019-12-19
期刊：
影响因子：
4.8
通讯作者：
Sun, Bei
中科院分区：
文献类型：
--
作者：
Li, Le;Tian, Feng-Yu;Sun, Bei
透明质酸酶1（HYAL-1）在胰十二指肠切除术（PD）术后胰瘘（POPF）发生中的主要机制尚不清楚。在本研究中，对可诱发 POPF 的两个队列（62 例胰腺癌 [PCa] 和 111 例胰腺导管腺癌 [PDAC]）的术前、术中和术后临床和生物学数据进行了全面的回顾性分析。然后，在PDAC组织中预测了总共7644个与HYAL-1相关的基因，并评估了这些相关基因的富集通路、激酶靶标和生物学过程。最后，首先建立小鼠胰瘘（PF）模型并进行体外研究以研究HYAL-1对PF进展的影响。我们的数据表明，术前血清HYAL-1水平、胰腺纤维化评分和胰管大小是检测B级和C级POPF的有价值的因素。建议将血清HYAL-1水平2.07 mg/ml和胰腺纤维化评分2.5作为提示POPF的临界值。生物信息学分析以及体外和体内研究表明，HYAL-1通过腺苷5'-单磷酸激活蛋白激酶（AMPK）和信号转导子和转录激活子3（STAT3）信号通路的去磷酸化促进胰腺腺泡细胞自噬，从而加剧胰腺分泌和炎症。总之，术前血清 HYAL-1 是 PD 患者发生 POPF 的重要预测因子。肿瘤诱导的HYAL-1是加速PF进而通过AMPK和STAT3诱导的自噬促进胰腺分泌和急性炎症反应的核心风险之一。
The main mechanism of hyaluronidase 1(HYAL-1) in the development of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) was unknown. In this study, a comprehensive inventory of pre-, intra-, and postoperative clinical and biological data of two cohorts (62 pancreatic cancer [PCa] and 111 pancreatic ductal adenocarcinoma [PDAC]) which could induce POPF were retrospectively analyzed. Then, a total of 7644 genes correlated with HYAL-1 was predicted in PDAC tissues and the enriched pathway, kinase targets and biological process of those correlated genes were evaluated. Finally, a mouse pancreatic fistula (PF) model was first built and in vitro studies were performed to investigate the effects of HYAL-1 on PF progression. Our data indicated that preoperative serum HYAL-1 level, pancreatic fibrosis score, and pancreatic duct size were valuable factors for detecting POPF of Grade B and C. The serum HYAL-1 level of 2.07 mg/ml and pancreatic fibrosis score of 2.5 were proposed as the cutoff values for indicating POPF. The bioinformatic analysis and in vitro and in vivo studies demonstrated that HYAL-1 facilitates pancreatic acinar cell autophagy via the dephosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) signaling pathways, which exacerbate pancreatic secretion and inflammation. In summary, the preoperative serum HYAL-1 was a significant predictor for POPF in patients who underwent PD. Tumor-induced HYAL-1 is one of core risk in accelerating PF and then promoting pancreatic secretion and acute inflammation response through the AMPK and STAT3-induced autophagy.