Research Progress on the Role and Potential of N6‑Methyladenosine

in Gastric Cancer Treatment

Ye He

Taiyuan Number 48 Middle School, Taiyuan, China

Keywords: N6‑methyladenosine (m6A), Gastric Cancer, Therapeutic Target.

Abstract: N6-methyladenosine (m6A) is the most prevalent RNA modification, playing a crucial role in RNA

metabolism, including stability, splicing, translation, and degradation. Dysregulation of m6A is involved in

gastric cancer (GC), affecting tumorigenesis, epithelial-mesenchymal transition(EMT), and chemotherapy

resistance. In GC, m6A modification promotes oncogene translation and alters non-coding RNA (ncRNA)

interactions, contributing to tumor proliferation, invasion, and therapy resistance. Overexpression of

METTL3 and YTHDF1 enhances m6A methylation which leads to MYC upregulation and EMT progression,

while FTO depletion stabilizes E-cadherin, suppressing tumor metastasis. Moreover, ncRNAs are

transcriptional modulators significantly affected by m6A modifications, influencing tumor growth and drug

resistance. Additionally, m6A regulates various forms of programmed cell death, including pyroptosis,

ferroptosis, autophagy, and cuproptosis, which indicates potential therapeutic target. Emerging strategies,

such as CRISPR-Cas9 and epigenetic modulation, offer new approaches for targeting m6A-related pathways.

Combining m6A-targeted therapies with conventional treatments may enhance GC outcomes, improving

patient quality of life and survival.

1 INTRODUCTION

N6-methyladenosine (m6A) is the most well-known

post-transcriptional RNA modification in mRNA

and non-coding RNAs. It plays an important role in

regulating RNA metabolism, including splicing,

stability, translation, and degradation. m6A is

dynamically formed by methyltransferases

(writers), removed by demethylases (erasers), and

recognized by binding proteins (readers). This

modification influences gene expression and has

been implicated in various physiological processes,

including embryonic development, immune

regulation, and tumor progression. In cancer, m6A

dysregulation changes oncogene and tumor

suppressor gene expression, affecting proliferation,

apoptosis, metastasis, and therapy resistance. As a

result, m6A is considered as a potential therapeutic

target in multiple cancers, including gastric cancer.

Gastric cancer (GC), also known as stomach cancer,

is a malignant tumor that originates from the lining

of the stomach. It is one of the most common

cancers around the world. Gastric cancer is

classified into different subtypes based on

histology, molecular characteristics, and location

within the stomach. The most common type is

adenocarcinoma, which accounts for more than

90% of cases. The primary risk factors for gastric

cancer include: Helicobacter pylori (H. pylori)

infection, a major cause of chronic inflammation

and lesions; unhealthy diet, such as high salt intake,

smoked foods, and low vegetable consumption;

lifestyle factors like smoking and alcohol abuse;

chronic gastritis and gastric ulcers, which may lead

to intestinal metaplasia and dysplasia. Genetic

factors also distribute to gastric tumorigenesis. It is

often diagnosed at an advanced stage due to vague

early symptoms, such as indigestion, mild

abdominal pain, or loss of appetite. This late

detection contributes to high mortality rates.

Gastric cancer is the fifth most common cancer

worldwide and the fourth leading cause of cancer-

related death. According to global cancer statistics,

it accounts for approximately one million new cases

and 770,000 deaths annually. The prognosis varies

based on the stage at diagnosis. Early-stage gastric

cancer has a five-year survival rate of over 90%

when treated with surgery; locally advanced gastric

cancer (spread to nearby lymph nodes) has a five-

year survival rate of 30–50%. Metastatic gastric

He, Y.

Research Progress on the Role and Potential of N6-Methyladenosine in Gastric Cancer Treatment.

DOI: 10.5220/0014486300004933

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 267-272

ISBN: 978-989-758-789-4

267

cancer (stage IV) has a five-year survival rate below

5–10%, since treatment options are limited.

Treatment for gastric cancer depends on the stage,

location, and molecular characteristics of the tumor.

For advanced and metastatic cases, systemic

therapy is required. First line treatment include

chemotherapy, basically platinum-based

chemotherapy combined with fluoropyrimidines.

Targeted Therapy are specially for HER2-positive

gastric cancer, and during this kind of therapy,

trastuzumab (Herceptin) is added to chemotherapy.

PD-1 inhibitors like pembrolizumab or nivolumab

are considered with chemotherapy for certain

patients with high PD-L1 expression. Second-Line

Chemotherapy is usually for those patients who had

worsened after first-line therapy, and taxane-based

(paclitaxel or docetaxel) or irinotecan-based drugs

are used. Ramucirumab (VEGFR-2 inhibitor),

either alone or with paclitaxel, improves survival in

second-line settings. Despite treatment advances,

chemotherapy resistance is still a major challenge,

highlighting the need for novel molecular-targeted

therapies, including those new findings on m6A

regulation.

2 THE MODIFICATIONS

INVOLVING M6A

m6A modification is dynamically regulated by three

groups of proteins: writers, erasers, and readers. The

initiation of m6A is mediated by the

methyltransferase complex, primarily composed of

METTL3 (methyltransferase-like 3) and METTL14,

along with accessory proteins such as WTAP (Wilms

tumor 1-associated protein), KIAA1429 (VIRMA),

RBM15, and ZC3H13. This complex catalyzes the

transfer of a methyl group to adenosine residues in

RNA, typically occurring within the RRACH

consensus motif (R = A/G, and H = A/C/U). Thanks

to the action of demethylases such as FTO (fat mass

and obesity-associated protein) and ALKBH5 (alkB

homolog 5), the activitiy of m6A could be altered

(Jiang et al. 2021, Hu et al. 2022). These enzymes

remove m6A marks, allowing for regulation of RNA

degradation and function. The biological effects of

m6A are mediated by reader proteins, which

recognize and bind to m6A-modified RNAs. The

YTH domain-containing family (YTHDF1,

YTHDF2, YTHDF3, and YTHDC1) determines the

fate of m6A-marked transcripts. Other readers, such

as IGF2BP1-3 (insulin-like growth factor 2 mRNA-

binding proteins) modulate RNA stability, translation

efficiency, and localization (Jiang et al. 2021, An &

Duan 2022).

The m6A modification impacts many aspects of

RNA metabolism: By recruiting the YTHDF2

protein, which promotes transcript decay through

interactions with the RNA decay machiner, m6A

promotes RNA degradation. m6A enhances

translation efficiency by recruiting initiation factors

such as eIF3 or promoting ribosome engagement

via YTHDF1.m6A could affect RNA splicing by

modulating interactions between splicing factors

and pre-mRNA, thereby affecting the selection of

exons (Jiang et al. 2021, An & Duan 2022). m6A

modification is also responsible to nuclear export of

transcripts, ensuring their proper localization inside

the cell. Regulating specific gene expressions, m6A

could mediate various kinds of physiological

functions, such as neuron differentiation, embryo

development and cancer formation. Dysregulation

of m6A modification has been associated with

various diseases, particularly cancer. Abnormal

m6A levels is associated to oncogenesis by altering

mRNA stability and expression of tumor suppressor

genes or oncogenes. Additionally, m6A

modifications influence other diseases such as

immune responses and metabolic disorders. As a

newly found promising therapeutic target, M6A has

significant clinical potential. Now researchers are

focused in exploring small-molecule inhibitors and

epigenetic editing techniques to modulate m6A-

related pathways.

3 THE DYSREGULATION OF

M6A FUNCTION IN GASTRIC

CARCINOGENESIS

METTL3,a crucial transmethylase, is widely known

because it is associated to tumor cell proliferation and

migration. Previous researches have found that

METTL3 is overly expressed in cancer cells. By

enhancing m6A methylation, MYC translation could

increase, leading to cancer cell proliferation.

Increased METTL3 levels indicate higher N-

cadherin/ Vimentin levels and lower E-cadherin

levels. The loss of E-cadherin shows the progression

of EMT, which is considered as a molecular marker

in cancer studies (Zeng et al. 2020, Wang et al. 2020).

Enhanced expression of HOXA10 caused by

excessive m6A methylation can also promote tumor

cell migration. Absence of FTO expression results in

the increase of E-cadherin and the decrease of

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vimentin. This indicates that FTO is related to

stabilization and expression in EMT related genes. In

the specific case of gastric cancer, higher EMT

expression levels could lead the transformation from

epilethial cells to mesenchymal cells (Wu et al. 2024).

By modulating the stability of mRNA, WTAP could

increase anaerobic glycolysis, which is a crucial

energy supply to cancer cells, since usually there are

less oxygen and higher temperature inside the tumor.

Over-expression of YTHDF1 is often found in gastric

cancer tissue In cases of resistance toward

chemotherapy drugs (Wu et al. 2024).

The demethylase, ALKBH5, specifically targets

the m6A modification on the mRNA of PKMYT1,

a protein kinase involved in cell cycle regulation.

The researchers demonstrated that its expression

was significantly lowered in gastric cancer tissues,

and low ALKBH5 levels correlated with poor

prognosis and increased cancer metastasis. This

means that ALKBH5 could be a potential

suppressor of gastric cancer metastasis. Through a

series of experiments, the study found that

ALKBH5 directly interacts with the m6A

modification site on the PKMYT1 mRNA.

ALKBH5’s demethylase activity could remove the

m6A modification from PKMYT1, thereby

stabilizing its mRNA and reducing its translation.

When overexpressed, PKMYT1 promotes cell

cycle. It has been linked to the increased motility

and invasion of cancer cells. The inhibition of

PKMYT1 expression by ALKBH5 limits the

metastasis of gastric cancer cells (Hu et al. 2022).

The researchers further corroborated this finding by

demonstrating that overexpressing ALKBH5 in

gastric cancer cells reduced cell invasion and

migration, while silencing ALKBH5 enhanced the

cells' invasive behavior. Additionally, they

observed that restoring PKMYT1 expression in

ALKBH5-overexpressing cells could partially

reverse the inhibition of cell invasion, so PKMYT1

is very probable to be a key mediator of ALKBH5.

These findings show the importance of the

interaction between ALKBH5 and PKMYT1 in

regulating the invasiveness of gastric cancer cells.

4 THE RELATIONSHIP

BETWEEN NCRNA AND M6A

There are mainly 3 types of noncoding RNA that

interact with m6A, including lncRNA, miRNA and

circRNA.

Long noncoding RNAs (lncRNA) are usually

described as RNA fragments longer than 200 bases

and they don’t have the ability to produce proteins,

but recent studies show that some of them do

encode microproteins that is essential in

physiological activities (Jin & Fan 2024).

Dysregulation of m6A could change the amount and

types of lncRNA, which may affect cell

proliferation, apoptosis and metastasis, eventually

leading to gastric cancer. Chemotherapy, the first

line medication for gastric cancer, faces a major

problem of drug resistance. Researchers found that

lncRNA-CBSLR could help tumor cells evade from

ferroptosis, protecting tumor cells in gastric cancer.

This results in chemoresistance. Another lncRNA,

ARHGAP5-AS1 is highly expressed in cancer cells,

and knocking down it could reverse this kind of

drug resistance. Also, high expression rate of

LNC942 is a signal of chemoresistant tumor cells in

gastric cancer. LNC942 can stabilize Myc mRNA,

and the upregulation of Myc would cause unlimited

proliferation of gastric cancer cells (Yang et al.

2021, Jin & Fan 2024).

MicroRNAs (miRNA) are small singular strands

of RNA. They consist of about 22 nucleotides.

Normally, miRNA acts as a transcription modulator

by binding base pairs with mRNA to interfere its

translation and promote degradation. Adenosine in

miRNAs could be modified as m6A, and research

shows that m6a plays an important role in

processing primary miRNA. The methylation of

specific sites within the pri-miRNA can promote or

inhibit the recognition of the transcript by Drosha,

an RNA enzyme which cuts unnecessary fragments

of primary miRNA. This regulation can determine

the levels of mature miRNAs suitable for post

transcriptional regulation. Some studies have

shown that METTL3, which adds m6A

modifications to RNA strands, can enhance or

suppress the maturation of certain pri-miRNAs,

thus modulating the expression of downstream

target genes that are involved in tumorigenesis.

Other numerous studies have shown miRNAs can

suppress the expression of m6A regulators,

resulting in alterations in m6A levels (Feng et al.

2023, Jayasree et al. 2024). In the cytoplasm,

mature miRNAs associate with RISC complexes to

silence the expression of target mRNAs. m6A

modifications on miRNAs can also influence their

interaction with RISC and the stability of the

miRNA-RISC complex. m6A-modified miRNAs

may change binding affinities for their target

mRNAs, affecting the efficiency of gene silencing.

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This mechanism has been linked to the regulation

of key genes involved in cancer progression. For

example, m6A modifications on the miRNA miR-

21, an oncogenic miRNA overexpressed in many

cancers, modulates its activity and influences the

expression of tumor suppressor genes such as

PTEN. This interaction between m6A and miRNA

regulation contributes to the complex regulation of

cancer cell behavior.

Circular RNAs (circRNA) are generated via

mRNA splicing and most of them are found in

cytoplasm. circRNA could act like a sponge to

absorb miRNA by competing binding sites with

mRNA, promoting specific gene expression. It

could also affect gene expression at the

transcriptional level, regulate variable splicing, and

participate in epigenetic regulations (Lin et al.

2022, Qin et al. 2021). While the functional role of

circRNAs in cancer has been widely studied, the

regulation of circRNAs by m6A modifications is a

relatively new area of research. m6A modification

affects the circularization of pre-mRNAs and can

impact the stability and translation of the resulting

circRNAs. In some cancers, m6A-modified

circRNAs may promote oncogenesis by stabilizing

certain transcripts, while in others, they may

function as tumor suppressors. These observations

suggest that the interaction between m6A and

circRNAs is highly variable and could be a critical

factor of cancer cell behavior. circRNAs are

associated with chemoresistance. circRNA could

regulate the expression of ABC transporters, which

pumps chemotherapy drugs out of cancer cells, and

it may be modified by m6A to enhance their

stability and promote drug resistance. Similarly,

circRNAs in the regulation of apoptosis and

autophagy can also be modulated by m6A to gain

resistance to chemotherapy induced cell death (Qin

et al. 2021).

5 THE POTENTIAL OF M6A AS A

THERAPEUTIC TARGET IN

GASTRIC CANCER

Pyroptosis is a special form of cell death driven by

gasdermin-mediated pore formation. When

inflammatory signals show pathogens or danger,

caspase-1 will be activated to lyse gasdermin, and the

product on the N terminal could perforate the cell

membrane, causing the cell to lyse. It has been shown

to be influenced by m6A modification. Dysregulation

of m6A regulators can alter pyroptotic signals in

tumor cells. Increased m6A methylation of specific

long noncoding RNAs may downregulate

inflammasome components, inhibiting pyroptosis

and favoring cancer cell survival. Therapeutic

interventions that upregulate m6A levels could

promote pyroptosis, and part of normal function of

cancer cells could be restored (Yang et al. 2023).

Autophagy is a cellular recycling process that is

associated with two aspects of cancer -- survival

under stress or cell death. In gastric cancer, m6A

modifications have been linked to the regulation of

autophagy-related genes (ATGs). Overexpression of

m6A writers such as METTL3 has been associated

with enhanced autophagy that supports tumor cell

survival and increases the possibility of

chemotherapy resistance. Conversely, inhibition of

specific m6A modifiers can disrupt overly active

autophagy, making cancer cells more sensitive to

conventional therapies (Wang et al. 2020, Yang et al.

2023). When the ROS reach lethal levels and the iron

ion is imbalanced in the cell, ferroptosis will start.

This is because glutathione peroxidase 4 (GPX4),

which is important for reducing peroxidized

membrane lipid, is inhibited and iron accelerates

peroxidation of lipid. m6A modification affects the

stability and translation of mRNAs encoding key

ferroptosis regulators, such as lncRNA-CBSLR,

SLC7A11 and GPX4. Modulating these targets, m6A

regulators can tip the balance between survival and

ferroptosis. Targeting the m6A machinery to induce

ferroptosis could be a novel approach to combat

chemoresistance in gastric cancer (Yang et al. 2021,

Yang et al. 2023).

More recent researches found the cell death,

cuproptosis, is induced by overload copper ions that

blocks TCA enzymes, causing loss of Fe-S clusters,

mitochondrial metabolism failure and proteotoxic

stress. m6A modifications can influence the

expression of cuproptosis related genes such as

FDX1, which are critical for copper induced toxicity.

Since gastric tumors often exhibit irregular copper

metabolism, targeting m6A pathways to promote

cuproptosis may provide a new strategy to kill tumor

cells which are resistant to other forms of cell death

(Yang et al. 2023).

Gene therapy could also help in treating gastric

cancer involving m6A. Advancements in CRISPR-

Cas9 gene editing have made precise manipulation of

m6A regulators easier and more precise. By

selectively knocking out or modulating m6A writers,

erasers or readers, researchers can analyse the roles of

these proteins in gastric tumor development. CRISPR

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screens have identified key m6A regulators whose

loss decreases tumor cell survival, finding new and

hopeful therapeutic targets (Kordyś et al. 2022, Tong

et al. 2021). Such approaches not only facilitate

functional studies but also provide a framework for

the development of gene therapies aimed at balancing

m6A levels. In epigenetics, m6A represents a

reversible mark that bridges genetic information and

post-transcriptional regulation. Specific m6A

patterns can lead to sustained oncogenic signaling and

contribute to the epigenetic plasticity of cancer cells

(Cusenza et al. 2023, Yue et al. 2023). Therapeutic

strategies that target m6A modifications can reverse

epigenetic deviations and restore normal gene

expression profiles. The integration of m6A targeted

drugs with epigenetic therapies could make gastric

cancer treatments more efficient.

6 CONCLUSION

Evidence shows the significance of m6A

modification in gastric cancer, influencing multiple

aspects of tumorigenesis, progression, and

therapeutic resistance. By modulating RNA stability,

translation, and interaction with non-coding RNAs

(lncRNA,miRNA and circRNA), m6A dynamically

shapes the cellular landscape of gastric tumors.

Dysregulation of m6A regulators can significantly

affect oncogene expression and tumor-suppressive

pathways, making it a promising target for novel

cancer therapies. Modulation of m6A levels could

enhance the effectiveness of existing treatments,

particularly by sensitizing cancer cells to

chemotherapy, regulating apoptosis, and inducing

various forms of programmed cell death, including

pyroptosis, ferroptosis, and cuproptosis. This could

be realized by the integration of m6A-targeted

therapies with CRISPR-based gene editing and

epigenetic modulators. In conclusion, targeting m6A

modification represents a novel and promising

strategy for gastric cancer therapy. Continued

research about the molecular mechanisms of m6A

and the development of specific inhibitors or

activators will be crucial in releasing its full

therapeutic potential. By integrating m6A-targeted

approaches with existing treatment modalities, the

future of gastric cancer management may gain

significant advancements, leading to improved

patient outcomes and higher survival rates.

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