整合荟萃分析中的代谢物与转录组学揭示了胰腺炎背景下 PDAC 中 SPHK1 的增强。

Integration of metabolites from meta-analysis with transcriptome reveals enhanced SPHK1 in PDAC with a background of pancreatitis.

机构信息

Asian Healthcare Foundation, Asian Institute of Gastroenterology, Mindspace Rd, Gachibowli, Hyderabad, Telangana, 500032, India.

AIG Hospitals, Mindspace Rd, Gachibowli, Hyderabad, Telangana, 500032, India.

出版信息

BMC Cancer. 2022 Jul 19;22(1):792. doi: 10.1186/s12885-022-09816-6.

DOI:10.1186/s12885-022-09816-6

PMID:35854233

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9295503/

Abstract

BACKGROUND

Pathophysiology of transformation of inflammatory lesions in chronic pancreatitis (CP) to pancreatic ductal adenocarcinoma (PDAC) is not clear.

METHODS

We conducted a systematic review, meta-analysis of circulating metabolites, integrated this data with transcriptome analysis of human pancreatic tissues and validated using immunohistochemistry. Our aim was to establish biomarker signatures for early malignant transformation in patients with underlying CP and identify therapeutic targets.

RESULTS

Analysis of 19 studies revealed AUC of 0.86 (95% CI 0.81-0.91, P < 0.0001) for all the altered metabolites (n = 88). Among them, lipids showed higher differentiating efficacy between PDAC and CP; P-value (< 0.0001). Pathway enrichment analysis identified sphingomyelin metabolism (impact value-0.29, FDR of 0.45) and TCA cycle (impact value-0.18, FDR of 0.06) to be prominent pathways in differentiating PDAC from CP. Mapping circulating metabolites to corresponding genes revealed 517 altered genes. Integration of these genes with transcriptome data of CP and PDAC with a background of CP (PDAC-CP) identified three upregulated genes; PIGC, PPIB, PKM and three downregulated genes; AZGP1, EGLN1, GNMT. Comparison of CP to PDAC-CP and PDAC-CP to PDAC identified upregulation of SPHK1, a known oncogene.

CONCLUSIONS

Our analysis suggests plausible role for SPHK1 in development of pancreatic adenocarcinoma in long standing CP patients. SPHK1 could be further explored as diagnostic and potential therapeutic target.

摘要

背景

慢性胰腺炎（CP）炎症病变向胰腺导管腺癌（PDAC）转化的病理生理学机制尚不清楚。

方法

我们进行了一项系统综述，对循环代谢物进行了荟萃分析，将这些数据与人类胰腺组织的转录组分析相结合，并通过免疫组织化学进行了验证。我们的目的是为基础 CP 患者的早期恶性转化建立生物标志物特征，并确定治疗靶点。

结果

对 19 项研究的分析显示，所有改变的代谢物（n=88）的 AUC 为 0.86（95%CI 0.81-0.91，P<0.0001）。其中，脂质在 PDAC 和 CP 之间具有更高的区分效力；P 值（<0.0001）。途径富集分析确定了鞘脂代谢（影响值-0.29，FDR 为 0.45）和 TCA 循环（影响值-0.18，FDR 为 0.06）是区分 PDAC 和 CP 的突出途径。将循环代谢物映射到相应的基因，发现了 517 个改变的基因。将这些基因与 CP 和 PDAC（CP 背景下的 PDAC）的转录组数据整合，发现了三个上调基因；PIGC、PPIB、PKM 和三个下调基因；AZGP1、EGLN1、GNMT。CP 与 PDAC-CP 和 PDAC-CP 与 PDAC 的比较发现 SPHK1 上调，SPHK1 是一种已知的癌基因。