SRGN-mediated reactivation of the YAP/CRISPLD2 axis promotes aggressiveness of hepatocellular carcinoma

Sep 23, 2026

Hepatocellular carcinoma (HCC) is a major contributor to global cancer-related mortality. Serglycin (SRGN) is involved in cancer progression, and its overexpression is linked to poor prognosis in HCC, yet its role in HCC aggressiveness remains unclear. This study identifies SRGN as a regulator of HCC cell migration and metastasis, promotes stemness-like traits, activates nuclear YAP, selectively upregulates CRISPLD2, and supports the SRGN/YAP/CRISPLD2 axis.

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Abstract

Introduction

Ivyspring International Publisher InternationalJournal of Biological Sciences 2025; 21(7): 3262-3285. doi: 10.7150/ijbs.108151 Research Paper SRGN-mediated reactivation of the YAP/CRISPLD2 axis promotes aggressiveness of hepatocellular carcinoma Shuqiao Zhang1*; Hao Hu1*; Xinyu Li1*; Qiuxia Chen2*; Yilu Zheng3; Huiting Peng1; Zhuomao Mo4; Wanting Hu5; Yantao Li1; Senkai Hong1; Bijun Huang6􀀍; Weihong Kuang1􀀍; Shijun Zhang2􀀍; Yang Cao1􀀍 1. First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. 2. Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. 3. Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. 4. Zhejiang University Medical Center, Zhejiang University, Hangzhou, Zhejiang, China. 5. Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai, China. 6. Sun Yat-sen University Cancer Center, Sun Yat-sen University Affiliated Tumor Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. *These authors have contributed equally to this work. 􀀍 Corresponding authors: Bijun Huang, [huangbj@sysucc.org.cn](huangbj@sysucc.org.cn); Weihong Kuang, kwh@[gzucm.edu.cn](gzucm.edu.cn); Shijun Zhang, [zhshjun@mail.sysu.edu.cn](zhshjun@mail.sysu.edu.cn); Yang Cao, [Caoyang0324@gzucm.edu.cn](Caoyang0324@gzucm.edu.cn). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2024.12.04; Accepted: 2025.04.16; Published: 2025.04.28 Abstract Hepatocellular carcinoma (HCC) is a major contributor to global cancer-related mortality. Serglycin (SRGN) is involved in the progression of various cancers, and its overexpression is related to poor prognosis in HCC patients. Its biological role in HCC aggressiveness is unknown. This study aims to elucidate the mechanism of SRGN in HCC. Via in vitro and vivo experiments, we identified SRGN as a critical regulator of HCC cells migratory capability and metastasis. SRGN significantly correlated with maintaining stemness-like characteristics, emphasizing its central role in HCC progression. Mechanistically, SRGN activated YAP into the tumor cells' nucleus. Moreover, SRGN selectively upregulated CRISPLD2, establishing the SRGN/YAP/CRISPLD2 axis and promoting metastatic behavior in HCC cells. Our results revealed that CRISPLD2 is a direct target of the SRGN-mediated YAP/TEAD1 complex. SRGN orchestrated stemness maintenance, tumorigenesis, and metastasis in an autocrine way by selectively reactivating the novel YAP/CRISPLD2 axis. Besides, sorafenib with verteporfin showed a certain therapeutic effect in SRGN-positive individuals. Our work clarifies the mechanism by which SRGN promotes the invasiveness of HCC. It provides insights into targeting the SRGN-triggered signaling pathway as a potential new direction in treating HCC. Keywords: Hepatocellular carcinoma; SRGN; Transcriptome; Tumor progression; CRISPLD2 Introduction Hepatocellular carcinoma (HCC) is a prevalent type of malignancy that contributes substantially to the global burden of cancer mortality[1] . Although surgical removal, liver transplantation, and ablation are recognized as curative options, many HCC patients are either not eligible for surgery or face recurrence due to the cancer's local spread or the development of metastases [2] . Proteoglycans, a class of macromolecules synthesized ubiquitously across cell types, are broadly classified into three categories, cell surface-associated proteoglycans, extracellular matrix (ECM)-secreted proteoglycans, and intracellular proteoglycans[3] . Emerging evid

FAQs

What question does the study address about SRGN in hepatocellular carcinoma?

The study investigates the biological role of SRGN in promoting aggressiveness in HCC, which had been unknown despite links to poor prognosis.

How does SRGN influence HCC progression according to the study?

SRGN increases HCC migratory ability and metastasis, maintains stemness-like characteristics, and activates a signaling mechanism involving YAP and CRISPLD2.

What is the proposed mechanism involving the YAP/CRISPLD2 axis?

SRGN activates YAP into tumor cell nuclei, selectively upregulates CRISPLD2, and forms an SRGN/YAP/CRISPLD2 axis that drives metastatic behavior.

Sep 23, 2026

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