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Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma
Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma
doi: 10.17265/2328-2150/2022.06.001
D DAVID PUBLISHING
Abstract: Objective: to search for hepatocellular carcinoma (HCC) in tumor subdivision from different aspects, such as transcripts,
proteins, gene mutations, protein interactions, signal pathways and functions. To explore the correlation between METTL1-6 protein
family and hepatocellular carcinoma (HCC), and to determine whether METTL family proteins are valuable as potential biomarkers
for tumor progression and prognosis of HCC. Methods: We try to use data collection technique to extract the data needed in medical
analysis. The correlation between the MRNA expression level of METTL family proteins and the prognosis of HCC patients was
obtained from TCGA data. METTL data and clinical data of protein METTL family in tissue samples of HCC patients were obtained
from Kaplan-Meier Plotter database for correlation analysis. The immunohistochemical data of METTL family protein 1, 2A, 2B, 3,
4, 5, 6 in normal liver tissue and HCC tissue were obtained from TIMER database. The protein network of METTL proteome was
obtained by using STRING database, and the heat map enrichment analysis of proteome interaction between KEGG and GO was
done by software. Results: 6 of the 7 METTL protein members were highly expressed in HCC tissues, and were positively correlated
with the grade and clinical analysis of HCC tumors.
Key words: METTL, hepatocellular carcinoma, tumor progression, prognosis, data collection, big data.
3.2 Analysis of the Relationship between Molecular PFS/DSS had a lower survival rate, especially in the
Expression and HCC Staging first three stages. As shown in Figure 6.
Figure 3 showed that the expression of selected 3.5 Data Analysis of the Relationship between
molecules in stage 1-3 was higher than that in stage 0, Molecular Expression and Immune Cell Infiltration
and was proportional to the grade (P < 0.01). It was
The immune cell infiltration of selected METTL
statistically significant, and the expression of selected
molecules in HCC patients participated in
METTL molecules increased with the progress of the
inflammatory response and immune cell infiltration,
disease. It is suggested that it can be used as a
thus affecting the clinical outcome of HCC patients.
potential marker of disease stage.
Therefore, we used TIMER database to study the
3.3 Data Analysis of the Relationship between relationship between differentially expressed METTL
Molecular Expression and HCC Grading chemokine and immune cell infiltration. The
expression of 7 kinds of METTL molecules selected
Figure 4 showed that the molecular expression of
were all correlated with the clearness of immune cells
1-4 grades was higher than 0 grades, and was
proportional to the grade (P < 0.01). It's statistically in stem cell carcinoma, and the correlation between
significant. It is suggested that the selected METTL METTL3 and METTL4 was the strongest. As shown
molecules are involved in the progression of HCC and in Figure 7.
can be used as a potential diagnostic marker for 3.6 Data Analysis Molecular Protein Interaction
grading the severity of the disease. Network and Enrichment Analysis
Besides the relationship between molecular
expression and TP53 gene mutation in HCC tissues, Construction and analysis of protein interaction
TP53 gene mutation is common in all kinds of tumors network of selected METTL molecules using STRING
and is an important tumorigenesis factor. Therefore, database (https://www.string-db.org/) to find the
the relationship between the expression of 7 molecules potential protein molecules that interact with
selected in TCGA database and TP53 gene mutation the selected METTL family molecules, and select the
in HCC tissues was further analyzed. The results of first 50 protein molecules to construct the PPI
data analysis (as shown in Figure 5) showed that the network map, and carry out GO and KEGG analysis,
expression of METTL1/METTL2B/METTL3/METTL4/ draw an enrichment analysis heat map. GO analysis
METTL5/METTL6 in mutated HCC tissues was showed that. The functional enrichment of the seven
significantly higher than that in TP53 non-mutated potential interacting proteins of METTL molecules is
HCC tissues (P < 0.0001). The expression of mainly related to ribonucleic acid metabolism, nucleic
METTL2A in mutated tissues was higher than that in acid activity catalysis, MRNA metabolism, RNA
non-mutated tissues (P < 0.01). The results were localization, ribonucleoprotein complex assembly,
statistically significant. positive regulation of telomere protein localization,
translation, ATP hydrolytic activity and chromatin
3.4 Data Analysis of the Relationship between
binding, which is also consistent with the results that
Molecular Expression and Survival and Prognosis
selected METTL molecules participate in gene
Among the 7 METTL molecules selected, the regulation by regulating protein expression. KEGG
patients with high expression of METTL1/METTL2A/ analysis showed that the selected METTL molecules
METTL3/METTL4/METTL5/METTL6 in OS/RFS/ were related to splice bodies, RNA transporters and
Clinical Significance
e of METTL Family
F Molecu
ules in Hepattocellular Carrcinoma 1777
OS
Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma 181
RFS
182 Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma
PFS
Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma 183
DSS
Fig. 6 Analysis of the relationship between the expression of METTL family molecules in tumor tissues and survival
prognosis of patients with HCC. Note: P < 0.05, the results were statistically significant.
184 Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma
Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma 185
186 Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma
Fig. 7 Analysis of the relationship between the expression of METTL family molecules and imm infiltration in tumor tissues of patients with HCC.
Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma 187
Fig. 8 Protein interaction network and thermographic enrichment analysis of METTL molecules.
ribosomal biogenesis in eukaryotes. This reflects that with the occurrence of HCC. It shows that the selected
the enrichment of the selected molecules in the members may potentially play an important regulatory
channels related to HCC has a positive relationship role in the occurrence of HCC. As shown in Figure 8.
188 Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma
4. Discussion and Conclusion a marker of HCC and as a basis for the prognosis of
the disease.
METTL3 as the first discovered M6A
In addition, with the progression of the disease,
methyltransferase (regulating the transcription and
patients with high expression of METTL family
translation of mRNA, which is closely related to
molecules had lower survival rates. These data suggest
carcinogenesis). Therefore, in recent years, METTL3,
that the seven METTL family molecules selected may
as the most concerned molecule in the METTL family,
play an important role in HCC. In view of the
has been found to be related to digestive tract cancer,
differences in the expression of various molecules in
prostate cancer, osteosarcoma and hematopoietic stem
HCC, we analyzed the data of GO and KEGG
cells [5]. With the discovery of more METTL family
pathways by enrichment analysis, and focused on the
molecules with technological advances, it has also
function of potential interacting proteins of selected
been confirmed that METTL family members are
METTL molecules. We found that METTL molecules
involved in other cancers [6-8]. However, the
are related to ribonucleic acid metabolism, nucleic
probability of gene mutation in HCC is higher, and
acid activity catalysis, MRNA metabolism, RNA
there is a potential interaction between METTL family
localization, ribonucleoprotein complex assembly,
molecules and TP53 [9]. UALCAN analysis showed
positive regulation of telomere protein localization,
that there was a high correlation between METTL1
translation, ATP hydrolysis activity and chromatin
expression of METTL family molecules in TCGA
binding. This happens to be related to the partial
database and cancer. The strategy of clinical diagnosis
occurrence channel of HCC. Previous studies have
and treatment of HCC is early diagnosis and early
shown that the METTL family is involved in m6A
treatment, and most of the methods rely on the
methyltransferase and mRNA transcription and
transformation of de-differentiate hepatoblast
translation, which is related to the progression of
progenitor cells into hepatocellular carcinoma cells to
various cancers. At the same time, the database results
express progenitor cells, or through the production of
suggest that the METTL molecular family can be used
iCCA [10]. The improvement of early diagnosis plays
as a potential target for drug therapy.
a decisive role in the prognosis of patients with HCC
Through the analysis of Oncomine and TCGA
[11].
database, it was found that 7 kinds of METTL family
The most important role of the METTL molecular
molecules (1/2A/2B/3/4/5/6) were highly expressed in
family is to form M6A methyltransferase, which
HCC tissues, and the survival rate of patients with
indirectly regulates protein production, and the
high expression was decreased. The selected METTL
METTL protein family forms an interaction group
family may be involved in the progression of
[12]. The expression of METTL family members is
hepatocellular carcinoma and can be used as one of
closely related to the occurrence of cancer [13-15]. In
the indicators for early diagnosis of hepatocellular
recent years, METTL18 has been proved to be a
carcinoma.
potential prognostic marker.
In this paper, we first analyzed the relationship Conflicts of Interest
between the expression, pathological grade and
The authors declare no conflict of interest.
staging of 7 kinds of METTL molecules and
hepatocellular carcinoma (HCC). We found that the References
expression of METTL in HCC patients was higher [1] Wang, W., & Wei, C. 2020. “Advances in the Early
than that in normal tissues, and was proportional to Diagnosis of Hepatocellular Carcinoma.” Genes Dis 7
each other. It is suggested that METTL can be used as (3): 308-319.
Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma 189