含HMG盒蛋白1（HBP1）在急性胰腺炎中可保护胰腺免受损伤，但会促进肿瘤进展。

HMG Box-containing Protein 1 (HBP1) Protects Against Pancreatic Injury in Acute Pancreatitis but Promotes Neoplastic Progression.

作者信息

Lee Seung-Won, Ekstrom Taelor, Manalo Elise C, Ye Shangyuan, Berry Mark, Grygoryev Dmytro, Szczepaniak Malwina, Lee Jinho, Marmolejo Carlos Origel, Haverlack Syber, Lee Juyoung, Shah Vidhi M, Keith Dove, Muschler John L, Chin Koei, Sears Rosalie C, Weisberg Stuart P, Morgan Terry, Kim Jungsun

机构信息

Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health and Science University (OHSU), School of Medicine, Portland, Oregon.

Biostatistics Shared Resource, Knight Cancer Institute, OHSU School of Medicine, Portland, Oregon.

出版信息

Cell Mol Gastroenterol Hepatol. 2025 May 20;19(9):101536. doi: 10.1016/j.jcmgh.2025.101536.

DOI:10.1016/j.jcmgh.2025.101536

PMID:40404099

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12242461/

Abstract

BACKGROUND & AIMS: Pancreatitis is an inflammatory disease of the exocrine pancreas and a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Previously, we identified HMG-box transcription factor 1 (HBP1) as a potential master transcription factor (TF) in the early progression of PDAC, with its expression associated with poor patient survival, underscoring its significance in pancreatic disease. However, the functional role of HBP1 in the onset and progression of acute pancreatitis (AP) remains unknown.

METHODS

We examined HBP1 expression in human pancreatitis samples and a cerulein-induced AP mouse model. Pancreatic-specific conditional HBP1 knockout mice, with or without an oncogenic Kras mutation, were generated and compared with their littermate controls. Spatial transcriptomics and multiplexed protein assays, histologic analysis, and immunostaining were utilized to characterize pathologic changes. Findings from mouse models were validated using inducible HBP1-overexpressing human pancreatic ductal epithelial cells.

RESULTS

HBP1 was upregulated in pancreatic exocrine cells in human chronic pancreatitis and mouse acute pancreatitis, with its expression in human chronic pancreatitis correlating with cancer presence. Pancreatic HBP1 ablation disrupted acinar homeostasis by impairing autophagic flux and exacerbating inflammation following injury. In the presence of oncogenic KRAS, HBP1 ablation delayed the formation of pancreatic intraepithelial neoplasia (PanIN), the precursor to PDAC, and slowed its progression to higher-grade lesions.

CONCLUSIONS

HBP1 upregulation in pancreatitis mitigates pancreatic inflammatory injury; however, in the presence of oncogenic KRAS, it facilitates PanIN progression. Thus, HBP1 serves as a critical regulator in both pancreatitis and early pancreatic neoplasia, representing a potential therapeutic target for intervening pancreatitis and PanIN progression.

摘要

背景与目的

胰腺炎是外分泌胰腺的一种炎症性疾病，也是胰腺导管腺癌（PDAC）的已知危险因素。此前，我们将HMG盒转录因子1（HBP1）鉴定为PDAC早期进展中一种潜在的主转录因子（TF），其表达与患者不良生存相关，突显了其在胰腺疾病中的重要性。然而，HBP1在急性胰腺炎（AP）发病和进展中的功能作用仍不清楚。

方法

我们检测了人胰腺炎样本和雨蛙肽诱导的AP小鼠模型中HBP1的表达。构建了有或没有致癌性Kras突变的胰腺特异性条件性HBP1基因敲除小鼠，并与它们的同窝对照进行比较。利用空间转录组学和多重蛋白质分析、组织学分析及免疫染色来表征病理变化。使用可诱导过表达HBP1的人胰腺导管上皮细胞验证小鼠模型的研究结果。

结果

HBP1在人慢性胰腺炎和小鼠急性胰腺炎的胰腺外分泌细胞中上调，其在人慢性胰腺炎中的表达与癌症存在相关。胰腺HBP1缺失通过损害自噬流和加重损伤后的炎症反应破坏腺泡内环境稳态。在存在致癌性KRAS的情况下，HBP1缺失延迟了胰腺上皮内瘤变（PanIN，PDAC的前体）的形成，并减缓其向高级别病变的进展。