HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma
Abstract Background Multiple myeloma (MM) is a malignancy of plasma cells that remains incurable. Toll-like receptor 4 (TLR4) acts as a stress-responsive signal, protecting mitochondria during proteasome inhibitor (PI) exposure, maintaining mitochondrial metabolism and increasing drug resistance in...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03750-8 |
| _version_ | 1798016790195863552 |
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| author | Lina Quan Chuiming Jia Yiwei Guo Yao Chen Xinya Wang Qiuting Xu Yu Zhang |
| author_facet | Lina Quan Chuiming Jia Yiwei Guo Yao Chen Xinya Wang Qiuting Xu Yu Zhang |
| author_sort | Lina Quan |
| collection | DOAJ |
| description | Abstract Background Multiple myeloma (MM) is a malignancy of plasma cells that remains incurable. Toll-like receptor 4 (TLR4) acts as a stress-responsive signal, protecting mitochondria during proteasome inhibitor (PI) exposure, maintaining mitochondrial metabolism and increasing drug resistance in MM. However, the mechanism of TLR4 regulation remains elusive. Aims The purpose of this study was to investigate the methylation pattern of multiple myeloma and its effect on the expression of HNRNPA2B1 and downstream targets. Methods The methylation level in MM and normal bone marrow specimens was detected using a colorimetric assay. HNRNPA2B1 gene knockdown was achieved in RPMI 8226 MM cells via adenovirus transfection. CCK8 and flow cytometric assays were used to detect proliferation and apoptosis, respectively. Transcriptome sequencing and m6A methylation MeRIP sequencing were applied, and differentially expressed genes (DEGs) were detected. Three independent NCBI GEO datasets were applied to examine the effects of HNRNPA2B1 and TLR4 expression on MM patient survival. Results HNRNPA2B1 promoted MM progression. Clinical data from database revealed that HNRNPA2B1 was adverse prognostic factor for survival among MM patients. Furthermore, transcriptome sequencing and methylation sequencing showed that HNRNPA2B1 recognized and was enriched at the m6A sites of TLR4 and TLR4 was down-regulated of both the m6A level and transcription level in HNRNPA2B1-knockdown MM cells. Moreover, TLR4 was an adverse survival prognostic factor based on database analysis. Conclusion Overall, our study implies that the RNA-binding protein HNRNPA2B1 increases cell proliferation and deregulates cell apoptosis in MM through TLR4 signaling. Our study suggests HNRNPA2B1 as a potential therapeutic target for MM. |
| first_indexed | 2024-04-11T15:56:23Z |
| format | Article |
| id | doaj.art-f9e4e947403848feadd7441543ab10ab |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-11T15:56:23Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-f9e4e947403848feadd7441543ab10ab2022-12-22T04:15:10ZengBMCJournal of Translational Medicine1479-58762022-11-0120111210.1186/s12967-022-03750-8HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myelomaLina Quan0Chuiming Jia1Yiwei Guo2Yao Chen3Xinya Wang4Qiuting Xu5Yu Zhang6Hematology Department, Harbin Medical University Cancer HospitalHematology Department, Harbin Medical University Cancer HospitalHematology Department, Harbin Medical University Cancer HospitalHematology Department, Harbin Medical University Cancer HospitalHematology Department, Harbin Medical University Cancer HospitalHematology Department, Harbin Medical University Cancer HospitalHematology Department, Harbin Medical University Cancer HospitalAbstract Background Multiple myeloma (MM) is a malignancy of plasma cells that remains incurable. Toll-like receptor 4 (TLR4) acts as a stress-responsive signal, protecting mitochondria during proteasome inhibitor (PI) exposure, maintaining mitochondrial metabolism and increasing drug resistance in MM. However, the mechanism of TLR4 regulation remains elusive. Aims The purpose of this study was to investigate the methylation pattern of multiple myeloma and its effect on the expression of HNRNPA2B1 and downstream targets. Methods The methylation level in MM and normal bone marrow specimens was detected using a colorimetric assay. HNRNPA2B1 gene knockdown was achieved in RPMI 8226 MM cells via adenovirus transfection. CCK8 and flow cytometric assays were used to detect proliferation and apoptosis, respectively. Transcriptome sequencing and m6A methylation MeRIP sequencing were applied, and differentially expressed genes (DEGs) were detected. Three independent NCBI GEO datasets were applied to examine the effects of HNRNPA2B1 and TLR4 expression on MM patient survival. Results HNRNPA2B1 promoted MM progression. Clinical data from database revealed that HNRNPA2B1 was adverse prognostic factor for survival among MM patients. Furthermore, transcriptome sequencing and methylation sequencing showed that HNRNPA2B1 recognized and was enriched at the m6A sites of TLR4 and TLR4 was down-regulated of both the m6A level and transcription level in HNRNPA2B1-knockdown MM cells. Moreover, TLR4 was an adverse survival prognostic factor based on database analysis. Conclusion Overall, our study implies that the RNA-binding protein HNRNPA2B1 increases cell proliferation and deregulates cell apoptosis in MM through TLR4 signaling. Our study suggests HNRNPA2B1 as a potential therapeutic target for MM.https://doi.org/10.1186/s12967-022-03750-8HNRNPA2B1TLR4Multiple myelomaN6-methyladenosine methylation |
| spellingShingle | Lina Quan Chuiming Jia Yiwei Guo Yao Chen Xinya Wang Qiuting Xu Yu Zhang HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma Journal of Translational Medicine HNRNPA2B1 TLR4 Multiple myeloma N6-methyladenosine methylation |
| title | HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma |
| title_full | HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma |
| title_fullStr | HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma |
| title_full_unstemmed | HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma |
| title_short | HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma |
| title_sort | hnrnpa2b1 mediated m6a modification of tlr4 mrna promotes progression of multiple myeloma |
| topic | HNRNPA2B1 TLR4 Multiple myeloma N6-methyladenosine methylation |
| url | https://doi.org/10.1186/s12967-022-03750-8 |
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