MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathway
<p dir="ltr">MicroRNAs (miRs/miRNAs) play a key role in posttranscriptional regulation of gene expression and are implicated in a number of physiological and pathological conditions, including cellular malignant transformation. In the current study, we investigated the role of miR-31...
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| مؤلفون آخرون: | , , , , , , , , , , , , , , |
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2020
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| _version_ | 1864513511251509248 |
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| author | Radhakrishnan Vishnubalaji (3563306) |
| author2 | Ramesh Elango (7542068) Muthurangan Manikandan (6002243) Abdul-Aziz Siyal (18619237) Dalia Ali (6002237) Ammar Al-Rikabi (5213753) Dana Hamam (3400181) Rimi Hamam (3563312) Hicham Benabdelkamel (2094556) Afshan Masood (8279052) Ibrahim O. Alanazi (3219180) Assim A. Alfadda (9674998) Musaad Alfayez (3571736) Abdullah Aldahmash (3563300) Moustapha Kassem (101848) Nehad M. Alajez (7397276) |
| author2_role | author author author author author author author author author author author author author author author |
| author_facet | Radhakrishnan Vishnubalaji (3563306) Ramesh Elango (7542068) Muthurangan Manikandan (6002243) Abdul-Aziz Siyal (18619237) Dalia Ali (6002237) Ammar Al-Rikabi (5213753) Dana Hamam (3400181) Rimi Hamam (3563312) Hicham Benabdelkamel (2094556) Afshan Masood (8279052) Ibrahim O. Alanazi (3219180) Assim A. Alfadda (9674998) Musaad Alfayez (3571736) Abdullah Aldahmash (3563300) Moustapha Kassem (101848) Nehad M. Alajez (7397276) |
| author_role | author |
| dc.creator.none.fl_str_mv | Radhakrishnan Vishnubalaji (3563306) Ramesh Elango (7542068) Muthurangan Manikandan (6002243) Abdul-Aziz Siyal (18619237) Dalia Ali (6002237) Ammar Al-Rikabi (5213753) Dana Hamam (3400181) Rimi Hamam (3563312) Hicham Benabdelkamel (2094556) Afshan Masood (8279052) Ibrahim O. Alanazi (3219180) Assim A. Alfadda (9674998) Musaad Alfayez (3571736) Abdullah Aldahmash (3563300) Moustapha Kassem (101848) Nehad M. Alajez (7397276) |
| dc.date.none.fl_str_mv | 2020-09-01T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41420-020-00312-z |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/MicroRNA-3148_acts_as_molecular_switch_promoting_malignant_transformation_and_adipocytic_differentiation_of_immortalized_human_bone_marrow_stromal_cells_via_direct_targeting_of_the_SMAD2_TGF_pathway/26232461 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Medical biotechnology Oncology and carcinogenesis MicroRNAs Stem Cells miR-3148 Adipocytic Differentiation Carcinogenesis Sarcoma Proteomic Analysis |
| dc.title.none.fl_str_mv | MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathway |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">MicroRNAs (miRs/miRNAs) play a key role in posttranscriptional regulation of gene expression and are implicated in a number of physiological and pathological conditions, including cellular malignant transformation. In the current study, we investigated the role of miR-3148 in regulating human stromal (mesenchymal) stem cell (hMSC) differentiation and transformation. Stable expression of miR-3148 in telomerized hMSC (hMSC-miR-3148) led to significant increase in in vitro adipocytic differentiation and suppression of osteoblastic differentiation. Concordantly, global gene expression profiling revealed significant enrichment in cholesterol biosynthesis pathway, and pathways related to enhanced cell movement and survival, whereas processes related to bone and connective tissue developments, cell death, apoptosis, and necrosis were downregulated. Global proteomic analysis using 2D-DIGE followed by mass spectrometry (MS) revealed significant changes in protein expression in hMSC-miR-3148 and enrichment in protein networks associated with carcinogenesis. Functional studies revealed that hMSC-miR-3148 exhibited enhanced in vitro cell proliferation, colony formation, migration, invasion, sphere formation, doxorubicin resistance, and increased active number of cells in S and G2/M cell cycle phases and formed sarcoma-like tumors with adipocyte infiltration when implanted into immunocompromised mice. SMAD2 was identified as bone fide gene target for miR-3148 using qRT-PCR, Western blotting, and UTR-based reporter assay. In agreement with our data, SMAD2 expression was downregulated in 47% of patients with soft tissue sarcoma. Bioinformatics analysis revealed that elevated miR-3148 expression correlates with poor prognosis in several human cancer types, including sarcoma. Our study identified miR-3148 as factor regulating hMSC differentiation and is involved in promoting malignant transformation of telomerized hMSC.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Death Discovery<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41420-020-00312-z" target="_blank">https://dx.doi.org/10.1038/s41420-020-00312-z</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_a8bb13ed0a55c4cfca6e0ed3258fc9fe |
| identifier_str_mv | 10.1038/s41420-020-00312-z |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26232461 |
| publishDate | 2020 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathwayRadhakrishnan Vishnubalaji (3563306)Ramesh Elango (7542068)Muthurangan Manikandan (6002243)Abdul-Aziz Siyal (18619237)Dalia Ali (6002237)Ammar Al-Rikabi (5213753)Dana Hamam (3400181)Rimi Hamam (3563312)Hicham Benabdelkamel (2094556)Afshan Masood (8279052)Ibrahim O. Alanazi (3219180)Assim A. Alfadda (9674998)Musaad Alfayez (3571736)Abdullah Aldahmash (3563300)Moustapha Kassem (101848)Nehad M. Alajez (7397276)Biological sciencesGeneticsBiomedical and clinical sciencesClinical sciencesMedical biotechnologyOncology and carcinogenesisMicroRNAsStem CellsmiR-3148Adipocytic DifferentiationCarcinogenesisSarcomaProteomic Analysis<p dir="ltr">MicroRNAs (miRs/miRNAs) play a key role in posttranscriptional regulation of gene expression and are implicated in a number of physiological and pathological conditions, including cellular malignant transformation. In the current study, we investigated the role of miR-3148 in regulating human stromal (mesenchymal) stem cell (hMSC) differentiation and transformation. Stable expression of miR-3148 in telomerized hMSC (hMSC-miR-3148) led to significant increase in in vitro adipocytic differentiation and suppression of osteoblastic differentiation. Concordantly, global gene expression profiling revealed significant enrichment in cholesterol biosynthesis pathway, and pathways related to enhanced cell movement and survival, whereas processes related to bone and connective tissue developments, cell death, apoptosis, and necrosis were downregulated. Global proteomic analysis using 2D-DIGE followed by mass spectrometry (MS) revealed significant changes in protein expression in hMSC-miR-3148 and enrichment in protein networks associated with carcinogenesis. Functional studies revealed that hMSC-miR-3148 exhibited enhanced in vitro cell proliferation, colony formation, migration, invasion, sphere formation, doxorubicin resistance, and increased active number of cells in S and G2/M cell cycle phases and formed sarcoma-like tumors with adipocyte infiltration when implanted into immunocompromised mice. SMAD2 was identified as bone fide gene target for miR-3148 using qRT-PCR, Western blotting, and UTR-based reporter assay. In agreement with our data, SMAD2 expression was downregulated in 47% of patients with soft tissue sarcoma. Bioinformatics analysis revealed that elevated miR-3148 expression correlates with poor prognosis in several human cancer types, including sarcoma. Our study identified miR-3148 as factor regulating hMSC differentiation and is involved in promoting malignant transformation of telomerized hMSC.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Death Discovery<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41420-020-00312-z" target="_blank">https://dx.doi.org/10.1038/s41420-020-00312-z</a></p>2020-09-01T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41420-020-00312-zhttps://figshare.com/articles/journal_contribution/MicroRNA-3148_acts_as_molecular_switch_promoting_malignant_transformation_and_adipocytic_differentiation_of_immortalized_human_bone_marrow_stromal_cells_via_direct_targeting_of_the_SMAD2_TGF_pathway/26232461CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/262324612020-09-01T00:00:00Z |
| spellingShingle | MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathway Radhakrishnan Vishnubalaji (3563306) Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Medical biotechnology Oncology and carcinogenesis MicroRNAs Stem Cells miR-3148 Adipocytic Differentiation Carcinogenesis Sarcoma Proteomic Analysis |
| status_str | publishedVersion |
| title | MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathway |
| title_full | MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathway |
| title_fullStr | MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathway |
| title_full_unstemmed | MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathway |
| title_short | MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathway |
| title_sort | MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFβ pathway |
| topic | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Medical biotechnology Oncology and carcinogenesis MicroRNAs Stem Cells miR-3148 Adipocytic Differentiation Carcinogenesis Sarcoma Proteomic Analysis |