Lactate activates CCL18 expression via H3K18 lactylation in macrophages to promote tumorigenesis of ovarian cancer - research article

Sep 21, 2026

Uploaded by Eden

This study investigates how lactate drives ovarian cancer development and progression and clarifies the molecular mechanism. Serum lactate levels correlate positively with tumor grade and poor prognosis, and bioinformatics implicates CCL18 as a lactate-related gene. CCL18 is up-regulated in tumor tissues and tracks with lactate levels. Lactate exposure induces macrophage M2 polarization, enhancing ovarian cancer cell proliferation and migration, which is reversed by Gpr132 silencing or anti-CCL18 antibody. In xenografts, tumor-promoting effects depend on Gpr132 and CCL18, while ChIP-qPCR and luciferase assays show lactate regulates CCL18 via H3K18 lactylation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

Introduction

Materials and Methods

Clinical sample collection

Bioinformatics analysis

Original Article Lactate activates CCL18 expression via H3K18 lactylation in macrophages to promote tumorigenesis of ovarian cancer Jinrui Sun1,2, Qinmei Feng1, Yue He2, Ming Wang2, and Yumei Wu2, * 1 Department of Gynecology, Shanxi Provincial People’s Hospital, Taiyuan 030001, China, and 2Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100006, China *Correspondence address. Tel: +86-15034401321; [E-mail:](E-mail: wym597118@ccmu.edu.cn)[ wym597118@ccmu.edu.cn](E-mail: wym597118@ccmu.edu.cn) Received 10 September 2023 Accepted 2 February 2024 Abstract This study investigates the role of lactate in the genesis and progression of ovarian cancer (OV) and explores the underlying mechanisms. Serum lactate levels show a positive correlation with tumor grade and poor prognosis inpatients with OV. Bioinformatics analysis identifies CCL18 as a lactate-related gene in OV. CCL18 is up-regulated in cancerous tissues and positively related to serum lactate levels in OV patients. THP-1 cells are exposed to phorbol- 12-myristate-13-acetate for M0 macrophage induction. The results of RT-qPCR and ELISA for M1/ M2 macrophagerelated markers and inflammatory cytokines show that the exposure of lactate to macrophages induces M2 polarization. Based on the coculture of OV cells with macrophages, lactate-treated macrophages induces a significant increase in the proliferation and migration of OV cells. However, these effects can be reversed by silencing of Gpr132 in macrophages or treatment with anti-CCL18 antibody. Experiments using the xenograft model verify that the oncogenic role of lactate in tumor growth and metastasis relies on Gpr132 and CCL18 . ChIP-qPCR and luciferase reporter assays reveal that lactate regulates CCL18 expression via H3K18 lactylation. In conclusion, lactate is a potential therapeutic target for OV. It is involved in tumorigenesis by activating CCL18 expression via H3K18 lactylation in macrophages. Key words ovarian cancer, lactate, macrophage, CCL18, lactylation Introduction Ovarian cancer (OV), the sixth most common tumor in women, is the leading cause of death among gynecological cancers, with more than 300,000 new cases reported in 2020 worldwide [1] . Despite considerable advances in treatment strategies, including surgery and combination chemotherapy, OV continues tobe associated with high mortality [2] . However, most patients with OV can be cured by currently available medication if they are diagnosed at early stages when the cancer is limited to the ovaries [3] . Therefore, further research is imperative to develop novel diagnostic and therapeutic strategies. In recent years, targeted therapies focusing on the tumor microenvironment (TME) have become a research hotspot [4,5] . Glycolysis is a major pathway of energy metabolism in cancer cells, and lactate is the end product of the glycolytic pathway [6] . In the TME, soluble molecules released by cancer cells, including lactate, can activate oncogenic signaling and modulate surrounding cells. This mechanism is believed to play a key role in cancer progression [7,8] . As an important component of the TME, tumor-associated macrophages (TAMs) account for approximately 10% of the total cells within the tumor stroma [9] . TAMs have also been implicated in the aggressive phenotypes of cancer cells [10,11] . The acquisition of the M2 phenotype by the TAMs, which has a tumor-promoting function, is linked to poor prognosis in the context of several types of cancers [12,13] . In the last decade, several studies have shown a close relationship between lactate and macrophage polarization in the setting of inflammation and cancer [14] . In a previous study, cancer-derived lactate was found to increase ROS levels and induce M2-like polarization of TAMs, thereby enhancing the epithelial-mesenchymal transition of cancer cells [15] . Using microf

FAQs

How does serum lactate relate to ovarian cancer outcomes in this study?

Serum lactate levels correlate positively with tumor grade and poor prognosis in ovarian cancer patients.

What effect does lactate have on macrophage polarization?

Lactate exposure induces macrophage M2 polarization, supported by RT-qPCR and ELISA measurements of M1/M2 markers and inflammatory cytokines.

How is CCL18 regulated by lactate in macrophages?

Lactate regulates CCL18 expression through H3K18 lactylation, as shown by ChIP-qPCR and luciferase reporter assays.

Sep 21, 2026

Uploaded by Eden