Nemati Marzieh, Dastghaib Sanaz, Hosseinzadeh Zahra, Molayem Mina, Siri Morvarid, Ebrahimi Bahareh, Bagheri Zohreh
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
BMC Cancer. 2025 Oct 3;25(1):1502. doi: 10.1186/s12885-025-14952-w.
The protein kinase RNA-like endoplasmic reticulum kinase (PERK) branch of the Unfolded Protein Response (UPR) plays a complex and context-dependent role in the colorectal cancer (CRC). While some studies indicate that PERK activation suppresses tumor growth by inducing apoptosis and limiting proliferation, others suggest that it may promote tumor progression by supporting cancer cell survival under stress. This systematic review aims to clarify the dual role of PERK signaling in CRC and evaluate its potential as a therapeutic target.
We included full-text English-language studies investigating the role of PERK signaling in CRC using in vitro and/or animal models. Studies on non-CRC malignancies or unrelated mechanisms were excluded. Searches were conducted in PubMed, Web of Science (WOS), and Scopus using relevant keywords.
A total of 395 articles were initially identified. After removing duplicates (n = 173), review articles (n = 11), and unrelated studies (n = 66), 45 studies met the inclusion criteria. Most of these (n = 36) used in vitro models, with the HCT-116 cell line being the most frequently used (n = 19). While most studies (n = 36) reported anti-tumorigenic effects associated with PERK activation, several identified conditions under which PERK signaling may support tumor progression. These conflicting findings may be attributed to differences in experimental models, PERK modulation strategies, and endoplasmic reticulum stress induction methods.
This review highlights the dual and context-dependent nature of PERK pathway activation in CRC. Although PERK often appears to exert tumor-suppressive effects, evidence also points to its tumor-promoting potential under certain conditions. A nuanced understanding of these roles is crucial for developing PERK-targeted therapies in CRC.
This systematic review has been registered in PROSPERO (International Prospective Register of Systematic Reviews) with the registration number CRD42023241342.
未折叠蛋白反应（UPR）中的蛋白激酶RNA样内质网激酶（PERK）分支在结直肠癌（CRC）中发挥着复杂且依赖于背景的作用。虽然一些研究表明PERK激活通过诱导凋亡和限制增殖来抑制肿瘤生长，但其他研究表明，它可能通过在应激条件下支持癌细胞存活来促进肿瘤进展。本系统评价旨在阐明PERK信号在CRC中的双重作用，并评估其作为治疗靶点的潜力。
我们纳入了使用体外和/或动物模型研究PERK信号在CRC中作用的全文英文研究。排除了关于非CRC恶性肿瘤或无关机制的研究。使用相关关键词在PubMed、科学网（WOS）和Scopus中进行检索。
最初共鉴定出395篇文章。在去除重复文章（n = 173）、综述文章（n = 11）和无关研究（n = 66）后，45项研究符合纳入标准。其中大多数（n = 36）使用体外模型，HCT-116细胞系是最常用的（n = 19）。虽然大多数研究（n = 36）报告了与PERK激活相关的抗肿瘤作用，但有几项研究确定了PERK信号可能支持肿瘤进展的条件。这些相互矛盾的发现可能归因于实验模型、PERK调节策略和内质网应激诱导方法的差异。
本综述强调了CRC中PERK通路激活的双重性和背景依赖性。虽然PERK通常似乎发挥肿瘤抑制作用，但证据也表明其在某些条件下具有促进肿瘤的潜力。对这些作用的细致理解对于开发针对CRC的PERK靶向治疗至关重要。
本系统评价已在国际前瞻性系统评价注册库PROSPERO中注册，注册号为CRD42023241342。
