m1A Regulator ALKBH1 and TRMT10B as Potential Prognostic Biomarkers and Related to Tumor Immune Microenvironment in Pancreatic Adenocarcinoma

doi:10.21203/rs.3.rs-1528350/v1

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m1A Regulator ALKBH1 and TRMT10B as Potential Prognostic Biomarkers and Related to Tumor Immune Microenvironment in Pancreatic Adenocarcinoma

https://doi.org/10.21203/rs.3.rs-1528350/v1

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Background N1-methyladenosine (m1A) RNA methylation is crucial in the carcinogenesis and tumorous molecular pathogenesis. However, the detailed pathogenic mechanism of m1A regulators in pancreatic adenocarcinoma (PAAD) has not been comprehensively researched. Therefore, the purpose of this study was to investigate the role of m1A in PAAD prognosis and tumor microenvironment (TME).

Methods The relationship between m1A regulators and the PAAD prognosis was analyzed with cBioportal database. RNA-seq transcriptome was obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases for differential expression analysis. The role of m1A regulators in the PAAD TME was analyzed with TISIDB database and R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed by The Database for Annotation, Visualization, and Integrated Discovery (DAVID).

Results In PAAD, we discovered 10 m1A regulators correlated to poor prognosis and were all upregulated. While up-regulated ALKBH1 and TRMT10B were associated with a better prognosis in PAAD patients. Further research found that ALKBH1 and TRMT10B significantly upregulated the infiltrating level of immune cells, especially CD4+ T cells. Additionally, they also affected the expression of immunomodulators, including CD276, TMEM173, TNFSF9, etc. Finally, GO and KEGG enrichment analysis proved that ALKBH1 and TRMT10B influenced the PAAD development by regulating the RNA polymerase II.

Conclusion Promoted expression of ALKBH1 and TRMT10B was significantly related with a better prognosis in PAAD, the possible mechanism of which might associate with the alternation of the TME. ALKBH1 and TRMT10B were potential prognosis biomarkers and possible immunotherapeutic targets for PAAD.

m1A modification

ALKBH1

TRMT10B

tumor microenvironment

prognostic biomarkers

pancreatic adenocarcinoma

Pancreatic adenocarcinoma (PAAD) is a highly malignant gastrointestinal tumor with a five-year survival rate of less than 7%(Miller, Ortiz et al. 2021). 80% of newly diagnosed PAAD patients cannot benefit from surgical resection, and their classical treatment options are cytotoxic chemotherapeutic agents such as gemcitabine and folfirinox(Von Hoff, Ervin et al. 2013). Due to the high tumor heterogeneity and malignant tumor microenvironment (TME), PAAD is susceptible to antigen loss evasion, widespread drug resistance, and severe adverse events during present chemotherapy(Grossberg, Chu et al. 2020, Melzer, Arnold et al. 2020, Zeng, Pöttler et al. 2019). In the case of ineffective chemotherapy, novel immunotherapy including tumor vaccines, immune checkpoint inhibitors (ICIs), and chimeric antigen receptor T-cell immunotherapy (CAR-T) are in development as potential therapies for PAAD(Chiorean and Coveler 2015, Schizas, Charalampakis et al. 2020).

Whole-exome sequencing of cancers uncovered an immunological glance in PAAD(Ren, Cui et al. 2018). It is dominated by the infiltration of immunosuppressive tumor-associated macrophages (TAMs) which can elevate METTL3 to promote oxaliplatin resistance(Lan, Liu et al. 2021). Current genetic analysis and immunophenotyping of PAAD patients have revealed few traditional prognostic biomarkers including tumor mutational load (TMB), programmed cell death protein 1, and CD8 (Knudsen, Vail et al. 2017). However, the current phase III clinical trials of these single-target tumor vaccines and ICIs have not achieved major endpoints(Schizas, Charalampakis et al. 2020). Moreover, microsatellite instability /defective DNA mismatch repair pancreatic ductal adenocarcinoma (PDAC) was shown to be the only PDAC disease subtype with potentially robust responsiveness to immunotherapy(Luchini, Brosens et al. 2021). The ultimate pathways of the targets used are focused on upregulating MHC-I molecules and CD8+ T cells to activate sufficient cytotoxic T lymphocyte (CTL) for antitumor effects, but ignore the fact that PAAD lacks CD8+ T cells in TME(Balachandran, Łuksza et al. 2017). Therefore, we urgently need to explore innovative sensitive biomarkers for a more accurate assessment of the TME status and patient prognosis in PAAD and corresponding potential targets for immunotherapy.

Compared with other malignancies, PAAD has a significant epigenetic background, which is the reason why it is highly susceptible to epithelial-mesenchymal transformation(Bararia, Dey et al. 2020, Knudsen, Vail et al. 2017). Among the more than 100 RNA molecules identified for post-transcriptional regulation, methylation modifications are the most common, often seen as an important epigenetic marker of PAAD(Brancaccio, Natale et al. 2019). Several genes (ppENK, p14, and APC) driving the progression of PAAD have been found to be characterized by hypermethylation of CpG islands(Bararia, Dey et al. 2020). The use of DNA demethylating drugs may lead to promising therapeutic strategies for early diagnosis and prognosis of PAAD(Bohnsack, Höbartner et al. 2019, Dominissini, Moshitch-Moshkovitz et al. 2012, Dominissini, Nachtergaele et al. 2016).

Among the methylation modifications, m1A, an RNA methylation modification on the N1 position of the molecule, is a new horizon of evolutionarily conserved and reversible transcriptomics regulation since the discovery of m6A methylation modification(Dominissini, Nachtergaele et al. 2016). The m1A/A ratio is up to 0.16% in tissues, and its mechanism and its function of post-transcriptional modification have inspired enthusiastic research (Dominissini, Nachtergaele et al. 2016). The post-transcriptional regulation of m1A is mainly regulated by "erasers" genes, "writers" genes, and "readers" genes(Frye, Harada et al. 2018). “Writers” (TRMT6, TRMT61A, TRMT10A, and TRMT10B) are cytoplasmic tRNA m1A methyltransferases regulating m1A levels and thus interfering with the translation process. “Readers” (YTHDF1, YTHDF2, YTHDF3, and YTHDC1) regulate post-transcriptional by preferentially binding to m1A-modified RNAs(Frye, Harada et al. 2018, Shi, Wei et al. 2019). “Erasers” (ALKBH1 and ALKBH3) catalyze the demethylation of m1A single-stranded nucleic acid to adenosine(Liu, Clark et al. 2016). ALKBH3 has been found to be a tRNA demethylase to promote the cleavage of demethylated tRNA by angiopoietin, thereby catalyzing the production of tRNA-derived small RNA, which positively induces protein synthesis in PAAD cells and interacts with cytochrome c to prevent the apoptotic process (Chen, Qi et al. 2019).

The m1A-related regulatory genes have been shown to correlate with the development of a variety of malignancies and may be utilized as potential molecular markers for clinical prognostic judgment. m1A-related enzymes can mediate the PI3K/AKT/mTOR pathways in five gastrointestinal (GI) cancers. Dysregulation or epigenetic alterations of m1A regulators especially ALKBH1 and TRMT10B may impact the formation and progression of GI(Zhao, Zhao et al. 2019). Researches have reported the promoted mutation frequency in m1A regulatory genes may be used as a marker of patient prognosis and is significantly associated with cancer stage and grade in PAAD (Wang, Wang et al. 2021). In particular, low expression of the ALKBH1 increases tumor invasion and metastasis, although the key downstream pathways and specific mechanisms are still unclear(Liu, Clark et al. 2016). However, the expression differences of m1A in PAAD patients and its correlation with immune response are largely understudied.

Therefore, in this study, we mainly analyzed PAAD patients’ clinicopathological and immunohistochemical information based on the Cancer Genome Atlas (TCGA), cBioPortal, OncoLnc, and other databases. Moreover, we found specific expression changes of 10 m1A regulators in PAAD, and then select ALKBH1 and TRMT10B to further study their correlation with immune infiltrating cells and immunomodulators. We also further speculated on the potential functions of m1A in cancer development by bioinformatics analysis. Our analyses suggested that m1A regulator ALKBH1 and TRMT10B are promising prognostic biomarkers and even immunotherapy targets for PAAD.

Expression analysis

Gene Expression Profiling Interactive Analysis (GEPIA) database (http://gepia.cancer-pku.cn/) is an online tool based on TCGA database https://portal.gdc.cancer.gov/) and Geno-type-Tissue Expression (GTEx) databases(https://www.gtexportal.org/) that provides rapid and customizable functionality including differential expression analysis, correlation analysis, analytical profiling, patient survival analysis. Transcriptome data from 178 PAAD and 171 normal pancreatic tissue samples in TCGA-PAAD and GTEx were included, after which the expression of m1A regulators in the data was analyzed via GEPIA and represented as box plots.

Survival analysis

CBioPortal (http://www.cbioportal.org/) is a public platform for exploration, visualization, and analysis of multi-dimensional cancer genomics and clinical data (Wu, Heins et al. 2019).In our research, the association between 10 m1A regulator variants and the survival time of PAAD patients was determined by cBioPortal. The samples were 1347 PAAD patients from 11 studies including Acinar Cell Carcinoma of the Pancreas (Jiao, Yonescu et al. 2014), and Cystic Tumor of the Pancreas (Wu, Jiao et al. 2011), etc.

The OncoLnc Database (http://www.oncolnc.org/) is an interactive tool for probing survival correlations and providing expression data for mRNAs, miRNAs, or long non-coding RNAs (lncRNAs) coupled to clinical data(Anaya 2016).In our study, the OncoLnc database was used to discover the correlation between the expression of specific m1A regulators and PAAD overall survival time. Both lower percentile and upper percentile were set to 50%.

Genetic alteration of m1A regulators in PAAD

The cBioPortal database gathers data from 126 tumor genomic studies. It can be used to visualize genetic alterations in samples from cancer studies and compare the frequency of genetic alterations and synthesize genomic alterations in a single sample. We used cBioPortal database to analyze the extent of variation in 10 m1A regulators from 1347 PAAD samples, the results of which were expressed as percentages. Types of genetic alteration included truncating mutation, inframe mutation, splice mutation, missense mutation, deep deletion, and amplification.

Immune response prediction

We used R software (version 3.6.3) to assess the correlation between m1A regulator expression and the levels of immune infiltration in PAAD samples, and the immune cells selected were B cells, CD4+ T cells, CD8+ T cells, DC cells, macrophages, and neutrophils (Bindea, Mlecnik et al. 2013). After we got the LEVEL 3 HTseq-FPKM format RNAseq data from TCGA database, we used GSVA package [version 1.34.0] in R to convert its FPKM format to TPM format, and log2 conversion was carried out (Hänzelmann, Castelo et al. 2013). P< 0.05 was considered that the immune cells were significantly associated with m1A regulators.

The TISIDB database (http://cis.hku.hk/TISIDB/index.php) is an online tool for the research of tumor-immune system interactions and it covers more than 30 tumor-related databases (Ru, Wong et al. 2019). In our research, TISIDB database was used to analyze the connection between the expression of m1A regulators and immune modulators (MHC molecules, immunostimulants, and immunosuppressants) in PAAD.

GO and KEGG enrichment analysis

The Database for Annotation, Visualization and Integrated Discovery (DAVID) (https://david.ncifcrf.gov/) is a database for differential analysis of genes, enrichment of pathways, and association to biological annotation(Kanehisa, Furumichi et al. 2017). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the co-expressed genes of m1A regulators to predict their potential functions with the DAVID database. P< 0.01 was considered as statistical significance for the study.

Statistics

P < 0.05 was statistically significant for all the above analyses if not otherwise stated in this research.

m1A regulators were correlated with prognosis in PAAD

We explored the association between m1A regulator aberrations and survival time of PAAD patients with the cBioPortal to assess the clinical significance of m1A regulators in PAAD. m1A regulator aberrations resulted in significantly shorter overall survival time (P<0.001) in PAAD patients (Fig. 1a) and remarkably shorter disease-free time (P<0.05) (Fig. 1b), both of which demonstrated that m1A regulators expression led to poorer prognosis in PAAD patients.

All m1A regulators had increased expression in PAAD

To verify the discrepancy in the expression of m1A regulators in PAAD and normal pancreatic tissue samples, we combined the GTEx and TCGA databases for further exploration. The results indicated the expression of 10 m1A regulators were increased in PAAD samples, including ALKBH1 (Fig. 2a), ALKBH3 (Fig. 2b), TRMT6 (Fig. 2c), TRMT10A (Fig. 2d), TRMT10B (Fig. 2e), TRMT61A (Fig. 2f), YTHDC1 (Fig. 2g), YTHDF1 (Fig. 2h), YTHDF2 (Fig. 2i), YTHDF3 (Fig. 2j) (P<0.01). Among them, ALBKH1 had the highest increase rate, which was about twice as high as normal samples.

m1A regulators were mutated, amplified, and deleted in PAAD

To confirm whether the differences in m1A regulator expression were associated with genetic variation, we used the cBioPortal database to examine the genetic variation of m1A regulators in 1347 PAAD patients. The results showed that all m1A regulators had varying degrees of missense mutations, amplifications, and deep deletions, which also indicated the anabatic expression of m1A regulators in PAAD patients was related to genetic variation (Fig. 3). Among these regulators, YTHDF1 and YTHDF3 had the highest frequency of mutations (1.6%), while TRMT10A and TRMT6 had the lowest frequency of mutations (0.4%). In terms of the types of mutations, m1A regulators were mainly amplificated, deleted and missense mutated, among which YTHDF1 and ALKBH3 were almost only amplificated, while YTHDF2 and YTHDC1 were almost only deleted.

High expression of ALKBH1 and TRMT10B was related to better prognosis in patients with PAAD

To further explore the correlation between the specific m1A regulators and the prognosis of PAAD patients, Kaplan-Meier plots were obtained from the OncoLnc database. The results revealed high expression of ALKBH1 (P=0.031) (Fig. 4a), and TRMT10B (P=0.002) (Fig. 4b) were significantly correlated with better prognosis in PAAD, which reflected that these two regulators played a vital role in PAAD development.

ALKBH1 and TRMT10B significantly upregulated the immune cell infiltration level in PAAD, especially CD4+ T cells

To understand what roles ALKBH1 and TRMT10B might play in the PAAD TME, we evaluated their relationship with immune infiltration. The results showed that ALKBH1 was observably related to CD4+ T cells (r=0.407, P<0.001), DC cells (r=0.167, P=0.026) (Fig. 5a). TRMT10B was significantly correlated with CD4+ T cells (r=0.208, P=0.005), CD8+ T cells (r=0.170, P=0.024) (Fig. 5b). This illustrated that ALKBH1 and TRMT10B significantly upregulated immune infiltration especially CD4+ T cells in PAAD.

ALKBH1 and TRMT10B affected the expression of immunomodulators in PAAD

To further investigate the effects of ALKBH1 and TRMT10B on the TME, we analyzed their correlation with immune modulators with the TISIDB database. We found that ALKBH1 was positively linked to immunoinhibitors (Fig. 6c), and was negatively linked to MHC molecules (Fig. 6a) and immunostimulators(Fig. 6b). TRMT10B was negatively associated with MHC molecules (Fig. 6a), immunostimulators (Fig. 6b), and immunoinhibitors (Fig. 6c). High ALKBH1 expression could significantly downregulate the expression of immunostimulators TMEM173 (r=-0.303, P=3.98e-05) (Fig. 7a), TNFSF9 (r=-0.311, P=2.43e-05) (Fig. 7b), CD276 (r=-0.404, P=2.79e-08) (Fig. 7c). TRMT10B significantly down-regulated the expression of immunostimulators TMEM173 (r=-0.312, P=2.27e-05) (Fig. 7h), CD276 (r=-0.458, P=1.74e-10) (Fig. 7j) and MHC molecule B2M (r=-0.311, P=2.43e-05) (Fig. 7d), and significantly up-regulated the expression of the immunoinhibitor CD160 (r=-0.312, P=2.27e-05) (Fig. 7f).

GO and KEGG enrichment analysis

GO and KEGG enrichment analysis was performed to explore the biological signaling pathways of ALKBH1 and TRMT10B influencing PAAD development. A total of 20 biological processes (Table 1), 7 cellular components (Table 2), and 13 molecular functions (Table 3) were enriched in GO enrichment analysis. We found these regulators were significantly enriched in regulation of transcription from RNA polymerase II promoter, protein binding, RNA polymerase II core promoter proximal region sequence-specific DNA binding (Fig. 8). A significant enrichment in the herpes simplex virus 1 infection pathway of these regulators was shown in the analysis of KEGG. RNA polymerase II had an essential role in the development of PAAD, indicating that ALKBH1 and TRMT10B might perform their function via regulating RNA polymerase II. The detailed information of KEGG enrichment results is listed in Table 4.

With a 5-year survival rate of less than 7% and heterogeneous clinical characteristics, it is a substantial challenge to treat pancreatic adenocarcinoma(Gupta, Amanam et al. 2017). Radiotherapy and chemotherapy have little effect on PAAD treatment and surgery is the main present treatment for PAAD but with poor prognosis (Wang, Zhang et al. 2021). Therefore, new immunotherapeutic strategies are in strong need for PAAD patients. m1A regulators play a vital role in the development of many tumors, which indicates their potential as prognosis biomarkers or even novel targets for the cancerous immunotherapy (Gao, Chen et al. 2021, Wu, Chen et al. 2021). Our study comprehensively investigated the prognostic value and effects on the immune microenvironment of m1A regulators in PAAD.

We firstly found that m1A regulators were significantly correlated to prognosis in PAAD. Then we demonstrated the expression of 10 m1A regulators ALKBH1, ALKBH3, TRMT6, TRMT10A, TRMT10B, TRMT61A, YTHDC1, YTHDF1, YTHDF2, and YTHDF3 were all increased in PAAD. Meanwhile, we confirmed that all these m1A regulators had diverse gene mutations in PAAD, which might explain why their expression was increased in PAAD. Among these 10 m1A regulators, YTHDF1 and YTHDF3 had the greatest degree of variation. Both YTHDF1 and YTHDF3 are m1A binding proteins, which play important roles in RNA folding, protein translation, and RNA metabolism(Liu, Li et al. 2020, Shi, Wang et al. 2017). It was revealed that these two proteins are associated with tumor development. By binding to m6A-modified EIF3C mRNA, YTHDF1 amplifies the translation of EIF3C in an m6A-dependent manner thereby facilitating tumorigenesis and metastasis of ovarian cancer(Liu, Wei et al. 2020). The negative feedback of YTHDF3 and glycolytic lncRNA DICER1-AS1 also participated in the tumorigenesis of PAAD(Hu, Tang et al. 2022). To further explore the correlation between the specific m1A regulators and the prognosis of PAAD, we got Kaplan-Meier plots using OncoLnc database. The results showed that among these 10 m1A regulators, ALKBH1 and TRMT10B were significantly associated with better prognosis in PAAD, indicating they play an important role in PAAD. As a demethylase, ALKBH1 has key functions in reversing DNA methylation and repairing DNA damage, acting as a substantial role in cancer development (Liu, Clark et al. 2016, Liu, Clark et al. 2016, Zhang and Wang 2021). Overexpression of ALKBH1 had the capacity to reverse the suppressive impacts of overexpressed miRNA-339-5p on proliferative and metastatic abilities in gastric carcinoma (Wang, Huang et al. 2020). Additionally, depletion of ALKBH1 in glioblastoma led to transcriptional silencing of oncogenic pathways through decreasing chromatin accessibility (Xie, Wu et al. 2018). In PAAD, it was reported that ALKBH1 could be involved in the development of PAAD by affecting mTOR and ErbB signaling pathways, and down-regulated ALKBH1 was correlated to the poor prognosis of PAAD patients(Zheng, Yu et al. 2021).TRMT10B is an RNA methyltransferase that has been identified as an m1A writer, and it is involved in modulating RNA stability, translation, splicing, decay, and Subcellular localization. TRMT10B was previously thought to have no impact on humans until it was proposed that TRMT10B had a restricted selectivity never seen in the Trm10 enzyme family (Howell, Jora et al. 2019). Whatever, few reports investigated the relationship between TRMT10B and tumors. We proposed for the first time that TRMT10B was related to the prognosis of PAAD patients, which was conducive to the follow-up research on the correlation between TRMT10B and other tumors.

A growing body of research suggests that immune infiltration in solid tumors is highly correlated with cancer prognosis, although the link is networked rather than absolute(Wang, Zou et al. 2021). In this study, we used R v3.6.3 to assess the relativity between m1A regulators and immune infiltration of PAAD, finding their potential to improve TME status and achieve the survival benefit of prolonging OS and progression-free survival in patients with PAAD.

ALKBH1 and TRMT10B could significantly upregulate infiltration levels of tumor-associated immune cells, particularly CD4+T cells. This appeared to share a common pathway with the immune signature of yes-associated protein 1, a recently discovered PAAD prognostic biomarker (Yang, Zheng et al. 2020). Previous personalized neoantigen targets selected for PAAD vaccines have mostly focused on CD8+T cells but with little success, which may be interpreted by the deficient CD8+ T cells’ infiltration and a predominance of M2 macrophages in the TME of PAAD(Balachandran, Łuksza et al. 2017, Yi, Hong et al. 2022, Balachandran, Beatty et al. 2019, Ren, Cui et al. 2018, Shi and Gao 2022). However, increasing evidence indicates that the selection of MHC-II neoantigen-mediated CD4+ T cells is also critical in killing tumors even distinct from CD8+ T cells. Also, their independent prognostic effect is better than TMB in many solid tumors such as bladder cancer and mammary adenocarcinoma.(Yi, Hong et al. 2022) Therefore, the new biomarkers ALKBH1 and TRMT10B that elevate CD4+T cells can be hopefully more sensitive clinical covariates to patients’ prognosis. CD4 helper T cells can also induce DCs migrating to lymph nodes, enhancing the presentation of tumor antigens (Cohen, Giladi et al. 2022). What’s more, gemcitabine-resistance in PAAD patients was ascertained to be associated with certain miRNA targeting that alters the ratio of memory CD4+ T cells(Gu, Zhang et al. 2020). These facts all suggest that ALKBH1 and TRMT10B, in addition to being potential targets in immunotherapy, may simultaneously provide synergy for reversing resistance to chemotherapeutic agents and enhancing the therapeutic efficacy of ICIs. They are as well promising a fresh perspective to address the conceptual challenges posed by negative outcomes of current PAAD mono-immunotherapies.

Due to the lack of studies on CD4+ T cells alterations with clinical relevance in long-term PAAD survivors, we firstly demonstrated the survival benefits of PAAD patients with high expression of ALKBH1 and TRMT10B might be associated with the increase in recruited CD4+ T cells and the adjusted ratio of tumor-infiltrating lymphocytes in TME.

ICIs have emerged as a powerful therapeutic strategy for multiple cancers, stimulating the innate and adaptive immune system, but with a poor prognosis in PAAD(Balachandran, Beatty et al. 2019). Our study found that high ALKBH1 expression downregulated the expression of immunomodulators CD276, TMEM173, and TNFSF9. TRMT10B could affect the expression of immunomodulators CD160, CD276, TMEM173, CD70, NT5E, TNFSF4, and the MHC molecule B2M. NO previous studies have demonstrated the signaling pathways of ALKBH1 and TRMT10B in the PAAD immune network. (Chen, Deng et al. 2021). Here, we firstly explored the interaction of immunomodulators closely related to ALKBH1 and TRMT10B with the immune system and their eventual relevance to the PAAD patient’s prognosis. The immunomodulator CD160 is an IgG-like glycoprotein expressed on the membranes of most peripheral blood circulating natural killer cells and γδT cells(Liu, Zhang et al. 2020). One study confirmed that infiltrating CD8+ T cells in PAAD highly expressed a CD160 subpopulation. Therefore, our study found that TRMT10B can elevate CD160 expression, thus ensuring a direct positive in-vitro antitumor effect and providing new ideas for CAR-T therapy. CD276, an immune checkpoint from the B7 superfamily, is highly expressed in TAMs and functionally suppressed DCs of TME. It can inhibit proliferation and activation of CTL, thus closely affecting tumor progression and metastasis(Geng, Huang et al. 2022). Therefore, our study suggested that ALKBH1 might improve the prognosis of PAAD patients by downregulating CD276 expression. TMEM173-dependent DNA sensor pathway was demonstrated to promote macrophage migration, activation, and malignant infiltration in PAAD, which indicated that TRMT10B could block the development of TMEM173-driven PAAD(Dai, Han et al. 2020). Other immunomodulators that we find could also be used as potential targets for immunotherapy. Our research indicated that ALKBH1 and TRMT10B signatures can reflect and improve TME features, thus holding hope for optimizing immunotherapy outcomes of PAAD.

To further determine the biological functions of ALKBH1 and TRMT10B in PAAD development, we performed GO and KEGG enrichment analysis(Chen, Zhang et al. 2017). The results indicated ALKBH1 and TRMT10B were enriched in the regulation of transcription from RNA polymerase II promoter, protein binding, RNA polymerase II core promoter sequence-specific DNA binding, and Herpes simplex virus 1 infection pathway. More studies have implicated that RNA polymerase II is significant in the development and treatment of PAAD(Ferdoush, Karmakar et al. 2017, Karmakar, Dey et al. 2018, Karmakar, Rauth et al. 2020, Liu, Gao et al. 2020). For example, regulating the nuclear localization of RNA polymerase II in pancreatic cancer cells represents a potential therapeutic target(Zhang, Li et al. 2021). Therefore, we speculate that ALKBH1 and TRMT10B may influence the development of PAAD by regulating RNA polymerase II. However, it needs further in vitro and in vivo validation in the direction of our future research.

Finally, we confirmed that ALKBH and TRMT10B were conducive to the prognosis of PAAD, and revealed their role in the tumor immune environment. Our study demonstrated that ALKBH1 and TRMT10 worked as prognosis biomarkers as well as potential immunotherapeutic targets for PAAD.

In conclusion, we demonstrated that 10 m1A regulators were abnormally expressed in PAAD and correlated with the PAAD prognosis. Additionally, we discovered that ALKBH1 and TRMT10B significantly upregulated the infiltrating level of immune cells and correlated with the expression of immunomodulators. ALKBH1 and TRMT10B could improve the TME of PAAD patients, thereby prolonging the survival time of patients. ALKBH1 and TRMT10B were potential prognosis biomarkers and possible immunotherapeuticaltic targets of PAAD.

Funding

This work is supported by the National College Students' innovation and entrepreneurship training program in China. (202110533026X) (XCX2021033)

Author contributions

JHL and SKH conceived the study and LHL carried out its design. Data collection and analysis were performed by JHL and SKH. The first draft of the manuscript was written by LHL, JHL, and SKH. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Data Availability

The datasets analysed during the current study are available in the GEPIA, (http://gepia.cancer-pku.cn/), TCGA, https://portal.gdc.cancer.gov/), OncoLnc,( http://www.oncolnc.org/), TISIDB, ( http://cis.hku.hk/TISIDB/index.php), DAVID,(https://david.ncifcrf.gov/),GTEx,(https://www.gtexportal.org/),cBioPortal,( http://www.cbioportal.org/).The datasets analyzed during the current study are available from the corresponding author on reasonable request. All relevant data are within the article and supporting material.

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Table 1 to 4 are available in the Supplemental Files section.

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m1A Regulator ALKBH1 and TRMT10B as Potential Prognostic Biomarkers and Related to Tumor Immune Microenvironment in Pancreatic Adenocarcinoma

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Abstract

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Introduction

Materials And Methods

Expression analysis

Survival analysis

Genetic alteration of m1A regulators in PAAD

Immune response prediction

GO and KEGG enrichment analysis

Statistics

Results

m1A regulators were correlated with prognosis in PAAD

All m1A regulators had increased expression in PAAD

m1A regulators were mutated, amplified, and deleted in PAAD

High expression of ALKBH1 and TRMT10B was related to better prognosis in patients with PAAD

ALKBH1 and TRMT10B significantly upregulated the immune cell infiltration level in PAAD, especially CD4+ T cells

ALKBH1 and TRMT10B affected the expression of immunomodulators in PAAD

GO and KEGG enrichment analysis

Discussion

Conclusion

Declarations

Funding

Author contributions

Competing Interests

Data Availability

References

Tables

Additional Declarations

Supplementary Files

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