MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis
Abstract Background Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic mo...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-022-01695-6 |
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| author | Parvez Khan Jawed Akhtar Siddiqui Prakash G. Kshirsagar Ramakanth Chirravuri Venkata Shailendra Kumar Maurya Tamara Mirzapoiazova Naveenkumar Perumal Sanjib Chaudhary Ranjana Kumari Kanchan Mahek Fatima Md Arafat Khan Asad Ur Rehman Imayavaramban Lakshmanan Sidharth Mahapatra Geoffrey A. Talmon Prakash Kulkarni Apar K. Ganti Maneesh Jain Ravi Salgia Surinder Kumar Batra Mohd Wasim Nasser |
| author_facet | Parvez Khan Jawed Akhtar Siddiqui Prakash G. Kshirsagar Ramakanth Chirravuri Venkata Shailendra Kumar Maurya Tamara Mirzapoiazova Naveenkumar Perumal Sanjib Chaudhary Ranjana Kumari Kanchan Mahek Fatima Md Arafat Khan Asad Ur Rehman Imayavaramban Lakshmanan Sidharth Mahapatra Geoffrey A. Talmon Prakash Kulkarni Apar K. Ganti Maneesh Jain Ravi Salgia Surinder Kumar Batra Mohd Wasim Nasser |
| author_sort | Parvez Khan |
| collection | DOAJ |
| description | Abstract Background Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. Methods To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. Results A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. Conclusions Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. Graphical Abstract MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis. |
| first_indexed | 2024-04-11T00:24:02Z |
| format | Article |
| id | doaj.art-70ed0bb8d596449cab613722670a3e36 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-04-11T00:24:02Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
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| series | Molecular Cancer |
| spelling | doaj.art-70ed0bb8d596449cab613722670a3e362023-01-08T12:06:15ZengBMCMolecular Cancer1476-45982023-01-0122112210.1186/s12943-022-01695-6MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axisParvez Khan0Jawed Akhtar Siddiqui1Prakash G. Kshirsagar2Ramakanth Chirravuri Venkata3Shailendra Kumar Maurya4Tamara Mirzapoiazova5Naveenkumar Perumal6Sanjib Chaudhary7Ranjana Kumari Kanchan8Mahek Fatima9Md Arafat Khan10Asad Ur Rehman11Imayavaramban Lakshmanan12Sidharth Mahapatra13Geoffrey A. Talmon14Prakash Kulkarni15Apar K. Ganti16Maneesh Jain17Ravi Salgia18Surinder Kumar Batra19Mohd Wasim Nasser20Department of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Medical Oncology and Therapeutics Research, City of Hope National Medical Center and Beckman Research InstituteDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Pathology and Microbiology, University of Nebraska Medical CenterDepartment of Medical Oncology and Therapeutics Research, City of Hope National Medical Center and Beckman Research InstituteDivision of Oncology-Hematology, Department of Internal Medicine, VA-Nebraska Western Iowa Health Care System, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Medical Oncology and Therapeutics Research, City of Hope National Medical Center and Beckman Research InstituteDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterAbstract Background Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. Methods To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. Results A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. Conclusions Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. Graphical Abstract MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.https://doi.org/10.1186/s12943-022-01695-6Small cell lung cancermicroRNAsCXCR4FOXM1RRM2Neuroendocrine carcinoma |
| spellingShingle | Parvez Khan Jawed Akhtar Siddiqui Prakash G. Kshirsagar Ramakanth Chirravuri Venkata Shailendra Kumar Maurya Tamara Mirzapoiazova Naveenkumar Perumal Sanjib Chaudhary Ranjana Kumari Kanchan Mahek Fatima Md Arafat Khan Asad Ur Rehman Imayavaramban Lakshmanan Sidharth Mahapatra Geoffrey A. Talmon Prakash Kulkarni Apar K. Ganti Maneesh Jain Ravi Salgia Surinder Kumar Batra Mohd Wasim Nasser MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis Molecular Cancer Small cell lung cancer microRNAs CXCR4 FOXM1 RRM2 Neuroendocrine carcinoma |
| title | MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis |
| title_full | MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis |
| title_fullStr | MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis |
| title_full_unstemmed | MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis |
| title_short | MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis |
| title_sort | microrna 1 attenuates the growth and metastasis of small cell lung cancer through cxcr4 foxm1 rrm2 axis |
| topic | Small cell lung cancer microRNAs CXCR4 FOXM1 RRM2 Neuroendocrine carcinoma |
| url | https://doi.org/10.1186/s12943-022-01695-6 |
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