Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Apr 15, 2025; 17(4): 99188
Published online Apr 15, 2025. doi: 10.4251/wjgo.v17.i4.99188
Impact of SLC16A8 on tumor microenvironment and angiogenesis in colorectal cancer: New therapeutic target insights
Hong-Peng Tian, Zhong-Xiang Xiao, Bo-Wen Su, Yi-Xuan Li, Hong Peng, Chang-Yuan Meng
Hong-Peng Tian, Zhong-Xiang Xiao, Bo-Wen Su, Chang-Yuan Meng, Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
Yi-Xuan Li, Department of Premarital and Prenatal Examination, Nanchong Shunqing District Maternal and Child Health Hospital, Nanchong 637000, Sichuan Province, China
Hong Peng, Department of Anorectal Surgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
Co-first authors: Hong-Peng Tian and Zhong-Xiang Xiao.
Co-corresponding authors: Hong Peng and Chang-Yuan Meng.
Author contributions: Tian HP, Peng H and Meng CY designed the experiments; Tian HP and Xiao ZX performed the experiments; Tian HP, Xiao ZX and Su BW collected the data and analyzed the data; Li YX validated the data analysis; Peng H and Meng CY provided funding support; Tian HP and Xiao ZX made equal contributions in experimental design, implementation, and data collection, and therefore are listed as co-first authors; Meng CY and Peng H are designated as co-corresponding authors due to their equal contributions in securing funding for the research project.
Supported by Nanchong Science and Technology Plan Project, No. 23JCYJPT0064; and Project of Sichuan Provincial Administration of Traditional Chinese Medicine, No. 2024MS590.
Institutional review board statement: All procedures involving clinical experiments were reviewed and approved by the Institutional Animal Care and Use Committee of the North Sichuan Medical Collage Institutional (Approval No. 2023-055).
Institutional animal care and use committee statement: The animal experiments were reviewed and approved by the North Sichuan Medical Collage Institutional Review Board (Approval No. 2021-44).
Conflict-of-interest statement: The authors declared that they had no conflicts of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Dataset available from the corresponding author at p1041910523@126.com.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hong Peng, Doctor, Department of Anorectal Surgery, Nanchong Central Hospital, The Second clinical Medical College, North Sichuan Medical College, No. 97 Renmin South Road, Shunqing District, Nanchong 637000, Sichuan Province, China. p1041910523@126.com
Received: July 16, 2024
Revised: November 8, 2024
Accepted: January 15, 2025
Published online: April 15, 2025
Processing time: 252 Days and 11.7 Hours
Abstract
BACKGROUND

SLC16A8, a lactate efflux transporter, is upregulated in various cancers, but its effects on tumor microenvironments remain understudied. This research explores its role in colorectal cancer (CRC) and the impact on the associated microenvironment consisting of vascular endothelial cells.

AIM

To explore the role in CRC and the impact on the associated microenvironment consisting of vascular endothelial cells.

METHODS

Hypoxic conditions prompted examination of SLC16A8 expression, glycolysis, lactate efflux, and Warburg effect correlations in CRC cell lines. Co-culture with HUVEC allowed for endothelial-mesenchymal transition (EndMT) characterization, revealing lactate efflux's influence. Knockdown of SLC16A8 in CRC cells enabled relevant phenotype tests and tumorigenesis experiments, investigating tumor growth, blood vessel distribution, and signaling pathway alterations.

RESULTS

SLC16A8 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues and correlated with disease progression (P < 0.05). Under hypoxic conditions, HIF-1α induced SLC16A8 expression, leading to enhanced metabolic reprogramming and increased lactate production. siRNA-mediated SLC16A8 knockdown effectively reversed hypoxia-induced changes, including reduced glucose consumption and lactate production. Co-culture experiments revealed that SLC16A8 knockdown significantly inhibited hypoxia-induced EndMT in HUVEC cells. In vivo studies demonstrated that SLC16A8 knockdown suppressed tumor growth, reduced Ki67 expression, and decreased HIF-1α levels. Furthermore, SLC16A8 silencing led to decreased expression of key metabolic enzymes PKM2 and LDHA, indicating its role in glycolytic regulation.

CONCLUSION

Our findings reveal that SLC16A8 functions as a critical mediator of hypoxia-induced metabolic reprogramming in CRC progression.

Keywords: SLC16A8; Colorectal cancer; Hypoxia; Glycolysis; Angiogenesis

Core Tip: Hypoxic SLC16A8 upregulated glycolysis factors in cancer cells. Co-culture with HUVEC increased endothelial-mesenchymal transition in endothelial cells. Knockdown reversed phenotypes in both cell types. In vivo, SLC16A8 inhibition reduced tumor growth and angiogenesis, and enhanced apoptosis.