Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2023; 29(40): 5543-5556
Published online Oct 28, 2023. doi: 10.3748/wjg.v29.i40.5543
Roles of phosphatidylinositol-3-kinases signaling pathway in inflammation-related cancer: Impact of rs10889677 variant and buparlisib in colitis-associated cancer
Nurul Nadirah Razali, Raja Affendi Raja Ali, Khairul Najmi Muhammad Nawawi, Azyani Yahaya, Norshafila Diana Mohd Rathi, Norfilza Mohd Mokhtar
Nurul Nadirah Razali, Norshafila Diana Mohd Rathi, Norfilza Mohd Mokhtar, Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
Raja Affendi Raja Ali, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia
Raja Affendi Raja Ali, Khairul Najmi Muhammad Nawawi, Norfilza Mohd Mokhtar, GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
Raja Affendi Raja Ali, Khairul Najmi Muhammad Nawawi, Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
Azyani Yahaya, Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
Author contributions: Mokhtar NM and Raja Ali RA contributed to the conceptualization; Mokhtar NM, Raja Ali RA, Muhammad Nawawi KN, and Razali NN contributed to the methodology and participant recruitments; Razali NN, and Mohd Rathi ND contributed to the animal handling; Razali NN, Yahaya A, and Mokhtar NM performed the validation; Razali NN, and Mokhtar NM contributed to the data analysis; Razali NN wrote the original draft preparation; Mokhtar NM, Raja Ali RA, and Muhammad Nawawi KN wrote the review and editing; Mokhtar NM, Raja Ali RA, and Muhammad Nawawi KN contributed to the supervision; All authors have read and agreed to the published version of the manuscript.
Supported by The Fundamental Research Grant Scheme, Ministry of Higher Education, Malaysia, No. FRGS/1/2018/SKK06/UKM/02/4.
Institutional review board statement: The human study has been approved under the Universiti Kebangsaan Malaysia Research Ethics Committee with a reference number: UKM/PPI/111/8/JEP-2019-572.
Institutional animal care and use committee statement: The animal study has been approved under the Animal Ethics Committee of Universiti Kebangsaan Malaysia with a reference number: PPUKM/2019/NORFILZA/25-SEPT./1035-SEPT.-2019-DEC.-2021 has approved the animal handling protocol.
Informed consent statement: Written informed consent was obtained from all the patients.
Conflict-of-interest statement: There is no conflict of interest.
Data sharing statement: Our raw data will be shared upon official request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Norfilza Mohd Mokhtar, PhD, Professor, Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras 56000, Kuala Lumpur, Malaysia. norfilza@ppukm.ukm.edu.my
Received: July 20, 2023
Peer-review started: July 20, 2023
First decision: August 25, 2023
Revised: September 5, 2023
Accepted: October 11, 2023
Article in press: October 11, 2023
Published online: October 28, 2023
ARTICLE HIGHLIGHTS
Research background

The phosphatidylinositol-3-kinases (PI3K)/AKT pathway has emerged as a potential new approach in the complicated landscape of inflammation-related cancer, providing new hope for patients with colitis-associated cancer (CAC). A recent discovery in the investigation of PI3K-related genes revealed a promising association between ulcerative colitis (UC), colorectal cancer (CRC), and the elusive rs10889677 mutation.

Research motivation

Understanding the involvement of the PI3K signalling pathway in the development and progression of CAC. Genetic Variants and CAC Susceptibility: Investigating the impact of genetic variants, such as the rs10889677 variant, on CAC susceptibility and their contribution to PI3K pathway activation. The potential of the pan-class I PI3K inhibitor buparlisib as a potential therapeutic option for the treatment of CAC was being examined.

Research objectives

To investigate the role of PI3K-related gene variation in CAC pathogenesis and to evaluate the therapeutic potential of buparlisib, a powerful pan-class I PI3K inhibitor with tumor-suppressive properties.

Research methods

The study examined the genomic DNA from 32 colonic samples from cases of CAC, UC, and CRC. The rs10889677 mutation was highlighted, which was amplified and cloned for both mutant and wild-type fragments in the pmirGLO vector. Luciferase activity was measured using the HT29 cell line. CAC was induced using a precise protocol that included azoxymethane and sodium dextran sulphate. Buparlisib was administered after 14 d. Immunohistochemistry for Ki67 and Cleaved-caspase-3 markers as well as quantitative real-time polymerase chain reaction for Pdk1 and Sgk2 were performed on excised colonic tissues.

Research results

Buparlisib significantly reduced the mean weight loss in these mice, indicating an increase in general health and well-being. It has an effect in slowing cancer cell development and promoting cell death in CAC-induced mice. It also had an effect on the expression of particular genes involved in the PI3K pathway, with significantly decreased Sgk2 expression and a decreasing trend in Pdk1 expression.

Research conclusions

Our study discovered that a specific genetic variant (rs10889677 variation) is critical in the activation of a cancer-promoting pathway known as PI3K. We also discovered that a drug called buparlisib can prevent this route from being triggered, which is great news for those fighting cancer (CAC).

Research perspectives

Patient stratification: Future research could look into whether the rs10889677 variant can be used as a biomarker to predict CAC development in UC patients. This could help with early detection and personalised treatment initiatives. Mechanism Elucidation: The mechanisms by which the rs10889677 variation alters the PI3K pathway should be studied further in the future.