A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasis
Abstract Background Metastasis is the major cause of morbidity and mortality in cancer that involves in multiple steps including epithelial–mesenchymal transition (EMT) process. Centrosome is an organelle that functions as the major microtubule organizing center (MTOC), and centrosome abnormalities...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-04-01
|
| Series: | Journal of Biomedical Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12929-022-00807-0 |
| _version_ | 1827284159508250624 |
|---|---|
| author | Yi-Wei Wang Shu-Chuan Chen De-Leung Gu Yi-Chen Yeh Jhih-Jie Tsai Kuo-Tai Yang Yuh-Shan Jou Teh-Ying Chou Tang K. Tang |
| author_facet | Yi-Wei Wang Shu-Chuan Chen De-Leung Gu Yi-Chen Yeh Jhih-Jie Tsai Kuo-Tai Yang Yuh-Shan Jou Teh-Ying Chou Tang K. Tang |
| author_sort | Yi-Wei Wang |
| collection | DOAJ |
| description | Abstract Background Metastasis is the major cause of morbidity and mortality in cancer that involves in multiple steps including epithelial–mesenchymal transition (EMT) process. Centrosome is an organelle that functions as the major microtubule organizing center (MTOC), and centrosome abnormalities are commonly correlated with tumor aggressiveness. However, the conclusive mechanisms indicating specific centrosomal proteins participated in tumor progression and metastasis remain largely unknown. Methods The expression levels of centriolar/centrosomal genes in various types of cancers were first examined by in silico analysis of the data derived from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and European Bioinformatics Institute (EBI) datasets. The expression of STIL (SCL/TAL1-interrupting locus) protein in clinical specimens was further assessed by Immunohistochemistry (IHC) analysis and the oncogenic roles of STIL in tumorigenesis were analyzed using in vitro and in vivo assays, including cell migration, invasion, xenograft tumor formation, and metastasis assays. The transcriptome differences between low- and high-STIL expression cells were analyzed by RNA-seq to uncover candidate genes involved in oncogenic pathways. The quantitative polymerase chain reaction (qPCR) and reporter assays were performed to confirm the results. The chromatin immunoprecipitation (ChIP)-qPCR assay was applied to demonstrate the binding of transcriptional factors to the promoter. Results The expression of STIL shows the most significant increase in lung and various other types of cancers, and is highly associated with patients’ survival rate. Depletion of STIL inhibits tumor growth and metastasis. Interestingly, excess STIL activates the EMT pathway, and subsequently enhances cancer cell migration and invasion. Importantly, we reveal an unexpected role of STIL in tumor metastasis. A subset of STIL translocate into nucleus and associate with FOXM1 (Forkhead box protein M1) to promote tumor metastasis and stemness via FOXM1-mediated downstream target genes. Furthermore, we demonstrate that hypoxia-inducible factor 1α (HIF1α) directly binds to the STIL promoter and upregulates STIL expression under hypoxic condition. Conclusions Our findings indicate that STIL promotes tumor metastasis through the HIF1α-STIL-FOXM1 axis, and highlight the importance of STIL as a promising therapeutic target for lung cancer treatment. |
| first_indexed | 2024-04-12T18:45:22Z |
| format | Article |
| id | doaj.art-80eda9faf5454279a945279d4da5e4a8 |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-04-24T09:51:09Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-80eda9faf5454279a945279d4da5e4a82024-04-14T11:23:56ZengBMCJournal of Biomedical Science1423-01272022-04-0129112310.1186/s12929-022-00807-0A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasisYi-Wei Wang0Shu-Chuan Chen1De-Leung Gu2Yi-Chen Yeh3Jhih-Jie Tsai4Kuo-Tai Yang5Yuh-Shan Jou6Teh-Ying Chou7Tang K. Tang8Institute of Biomedical Sciences, Academia SinicaInstitute of Biomedical Sciences, Academia SinicaInstitute of Biomedical Sciences, Academia SinicaDepartment of Pathology and Laboratory Medicine, Taipei Veterans General HospitalInstitute of Biomedical Sciences, Academia SinicaInstitute of Biomedical Sciences, Academia SinicaInstitute of Biomedical Sciences, Academia SinicaDepartment of Pathology and Laboratory Medicine, Taipei Veterans General HospitalInstitute of Biomedical Sciences, Academia SinicaAbstract Background Metastasis is the major cause of morbidity and mortality in cancer that involves in multiple steps including epithelial–mesenchymal transition (EMT) process. Centrosome is an organelle that functions as the major microtubule organizing center (MTOC), and centrosome abnormalities are commonly correlated with tumor aggressiveness. However, the conclusive mechanisms indicating specific centrosomal proteins participated in tumor progression and metastasis remain largely unknown. Methods The expression levels of centriolar/centrosomal genes in various types of cancers were first examined by in silico analysis of the data derived from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and European Bioinformatics Institute (EBI) datasets. The expression of STIL (SCL/TAL1-interrupting locus) protein in clinical specimens was further assessed by Immunohistochemistry (IHC) analysis and the oncogenic roles of STIL in tumorigenesis were analyzed using in vitro and in vivo assays, including cell migration, invasion, xenograft tumor formation, and metastasis assays. The transcriptome differences between low- and high-STIL expression cells were analyzed by RNA-seq to uncover candidate genes involved in oncogenic pathways. The quantitative polymerase chain reaction (qPCR) and reporter assays were performed to confirm the results. The chromatin immunoprecipitation (ChIP)-qPCR assay was applied to demonstrate the binding of transcriptional factors to the promoter. Results The expression of STIL shows the most significant increase in lung and various other types of cancers, and is highly associated with patients’ survival rate. Depletion of STIL inhibits tumor growth and metastasis. Interestingly, excess STIL activates the EMT pathway, and subsequently enhances cancer cell migration and invasion. Importantly, we reveal an unexpected role of STIL in tumor metastasis. A subset of STIL translocate into nucleus and associate with FOXM1 (Forkhead box protein M1) to promote tumor metastasis and stemness via FOXM1-mediated downstream target genes. Furthermore, we demonstrate that hypoxia-inducible factor 1α (HIF1α) directly binds to the STIL promoter and upregulates STIL expression under hypoxic condition. Conclusions Our findings indicate that STIL promotes tumor metastasis through the HIF1α-STIL-FOXM1 axis, and highlight the importance of STIL as a promising therapeutic target for lung cancer treatment.https://doi.org/10.1186/s12929-022-00807-0MetastasisSTILFOXM1HIF1αCentrosome |
| spellingShingle | Yi-Wei Wang Shu-Chuan Chen De-Leung Gu Yi-Chen Yeh Jhih-Jie Tsai Kuo-Tai Yang Yuh-Shan Jou Teh-Ying Chou Tang K. Tang A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasis Journal of Biomedical Science Metastasis STIL FOXM1 HIF1α Centrosome |
| title | A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasis |
| title_full | A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasis |
| title_fullStr | A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasis |
| title_full_unstemmed | A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasis |
| title_short | A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasis |
| title_sort | novel hif1α stil foxm1 axis regulates tumor metastasis |
| topic | Metastasis STIL FOXM1 HIF1α Centrosome |
| url | https://doi.org/10.1186/s12929-022-00807-0 |
| work_keys_str_mv | AT yiweiwang anovelhif1astilfoxm1axisregulatestumormetastasis AT shuchuanchen anovelhif1astilfoxm1axisregulatestumormetastasis AT deleunggu anovelhif1astilfoxm1axisregulatestumormetastasis AT yichenyeh anovelhif1astilfoxm1axisregulatestumormetastasis AT jhihjietsai anovelhif1astilfoxm1axisregulatestumormetastasis AT kuotaiyang anovelhif1astilfoxm1axisregulatestumormetastasis AT yuhshanjou anovelhif1astilfoxm1axisregulatestumormetastasis AT tehyingchou anovelhif1astilfoxm1axisregulatestumormetastasis AT tangktang anovelhif1astilfoxm1axisregulatestumormetastasis AT yiweiwang novelhif1astilfoxm1axisregulatestumormetastasis AT shuchuanchen novelhif1astilfoxm1axisregulatestumormetastasis AT deleunggu novelhif1astilfoxm1axisregulatestumormetastasis AT yichenyeh novelhif1astilfoxm1axisregulatestumormetastasis AT jhihjietsai novelhif1astilfoxm1axisregulatestumormetastasis AT kuotaiyang novelhif1astilfoxm1axisregulatestumormetastasis AT yuhshanjou novelhif1astilfoxm1axisregulatestumormetastasis AT tehyingchou novelhif1astilfoxm1axisregulatestumormetastasis AT tangktang novelhif1astilfoxm1axisregulatestumormetastasis |