The role and mechanism of FTO in the occurrence and development of gastrointestinal malignancies and research progress in its applications
10.7659/j.issn.1005-6947.2024.10.018
- VernacularTitle:FTO在胃肠道恶性肿瘤发生发展中的作用机制及应用研究进展
- Author:
Hao CHEN
1
;
Yuanliang LI
;
Haogang ZHANG
;
Pengfei QIAO
Author Information
1. 哈尔滨医科大学附属第二医院普通外科,黑龙江哈尔滨 150081
- Keywords:
Digestive System Neoplasms;
Stomach Neoplasms;
Colorectal Neoplasms;
Methylation;
Fat Mass and Obesity Asso-ciated Protein;
Review
- From:
Chinese Journal of General Surgery
2024;33(10):1714-1723
- CountryChina
- Language:Chinese
-
Abstract:
Gastrointestinal malignant tumors are common worldwide,particularly gastric cancer(GC)and colorectal cancer(CRC),with complex and not fully understood molecular mechanisms behind their occurrence and progression.Treatment typically involves a comprehensive approach centered on surgery,which,despite achieving good outcomes,still faces challenges due to high recurrence rates and low survival rates impacting patient health.N6-methyladenosine(m6A)is the most abundant internal modification in mRNAs and plays a crucial role in regulating RNA post-transcriptional modifications and downstream functions.Fat mass and obesity-associated protein(FTO)was the first identified m6A demethylase capable of removing dynamic,reversible m6A modifications.During the development of gastrointestinal malignancies,FTO regulates the expression of specific genes,affecting tumor cell proliferation and metastasis;modulates the expression of tumor-related cytokines and immune-related molecules,influencing the tumor microenvironment;and plays a significant role in sensitivity and resistance to chemotherapy.FTO is upregulated in most types of GC,indicating poor prognosis.High FTO expression enhances GC cell migration and invasion,increases chemoresistance,promotes tumor stem cell proliferation and differentiation,and inhibits apoptosis,thus facilitating GC progression.In CRC,many studies show that FTO is upregulated in tissues and cells,promoting CRC progression by enhancing cell proliferation,migration,invasion,and resistance to chemotherapy.Low FTO expression can also elevate m6Am levels in CRC cell cytoplasmic mRNA,promoting tumor stem cell proliferation,differentiation,tumor formation,and increasing resistance.In contrast,high FTO expression inhibits tumor stem cell proliferation and differentiation.FTO is also upregulated in other gastrointestinal tumors like pancreatic and esophageal cancers,where high expression promotes progression and indicates poor prognosis.FTO has both promoting and inhibitory effects on liver and biliary malignancies.As research confirms FTO's widespread oncogenic role in the gastrointestinal tract,developing FTO inhibitors and related drugs offers new avenues for treating gastrointestinal malignancies.Currently identified agents like CS1,omeprazole,and mupirocin significantly inhibit CRC and GC progression by directly or indirectly suppressing FTO.Tumors can evade immune surveillance through FTO-mediated mechanisms,suggesting that blocking FTO-mediated immune escape and enhancing the antitumor effects of immune cells could provide treatment options for gastrointestinal malignancies.Targeting FTO in combination with immunotherapy to inhibit GC and CRC growth and metastasis and reduce resistance presents broad therapeutic prospects.
