Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-β2 signaling
Abstract Background Ovarian cancer has the highest mortality among gynecological cancers due to late diagnosis and lack of effective targeted therapy. Although the study of interplay between cancer cells with their microenvironment is emerging, how ovarian cancer triggers signaling that coordinates...
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Journal of Biomedical Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12929-022-00888-x |
| _version_ | 1797774012260024320 |
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| author | Sheng-Chieh Lin Yi-Chu Liao Po-Ming Chen Ya-Yu Yang Yi-Hsiang Wang Shiao-Lin Tung Chi-Mu Chuang Yu-Wen Sung Te-Hsuan Jang Shuang-En Chuang Lu-Hai Wang |
| author_facet | Sheng-Chieh Lin Yi-Chu Liao Po-Ming Chen Ya-Yu Yang Yi-Hsiang Wang Shiao-Lin Tung Chi-Mu Chuang Yu-Wen Sung Te-Hsuan Jang Shuang-En Chuang Lu-Hai Wang |
| author_sort | Sheng-Chieh Lin |
| collection | DOAJ |
| description | Abstract Background Ovarian cancer has the highest mortality among gynecological cancers due to late diagnosis and lack of effective targeted therapy. Although the study of interplay between cancer cells with their microenvironment is emerging, how ovarian cancer triggers signaling that coordinates with immune cells to promote metastasis is still elusive. Methods Microarray and bioinformatics analysis of low and highly invasive ovarian cancer cell lines were used to reveal periostin (POSTN), a matrix protein with multifunctions in cancer, with elevated expression in the highly invasive cells. Anchorage independent assay, Western blot, RNA interference, confocal analysis and neutralizing antibody treatment were performed to analyze the effects of POSTN on tumor promotion and to explore the underlying mechanism. Chemotaxis, flow cytometry and cytokine array analyses were undertaken to analyze the involvement of POSTN in cancer-associated fibroblast (CAF) and macrophage modulation. Correlations between POSTN expression levels and clinical characteristics were analyzed using the Oncomine, commercial ovarian cancer cDNA and China Medical University Hospital patient cohort. In vivo effect of POSTN on metastasis was studied using a mouse xenograft model. Results Expression of POSTN was found to be elevated in highly invasive ovarian cancer cells. We observed that POSTN was co-localized with integrin β3 and integrin β5, which was important for POSTN-mediated activation of ERK and NF-κB. Ectopic expression of POSTN enhanced whereas knockdown of POSTN decreased cancer cell migration and invasion in vitro, as well as tumor growth and metastasis in vivo. POSTN enhanced integrin/ERK/NF-κB signaling through an autocrine effect on cancer cells to produce macrophage attracting and mobilizing cytokines including MIP-1β, MCP-1, TNFα and RANTES resulting in increased chemotaxis of THP-1 monocytes and their polarization to M2 macrophages in vitro. In agreement, tumors derived from POSTN-overexpressing SKOV3 harbored more tumor-associated macrophages than the control tumors. POSTN induced TGF-β2 expression from ovarian cancer cells to promote activation of adipose-derived stromal cells to become CAF-like cells expressing alpha smooth muscle actin and fibroblast activation protein alpha. Consistently, increased CAFs were observed in POSTN overexpressing SKOV3 cells-derived metastatic tumors. In clinical relevance, we found that expression of POSTN was positively correlated with advanced-stage diseases and poor overall survival of patients. Conclusions Our study revealed a POSTN-integrin-NF-κB-mediated signaling and its involvement in enhancing M2 macrophages and CAFs, which could potentially participate in promoting tumor growth. Our results suggest that POSTN could be a useful prognosis marker and potential therapeutic target. |
| first_indexed | 2024-03-12T22:14:46Z |
| format | Article |
| id | doaj.art-4091e35327aa44ed87ac21be9b28eec1 |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-03-12T22:14:46Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-4091e35327aa44ed87ac21be9b28eec12023-07-23T11:21:49ZengBMCJournal of Biomedical Science1423-01272022-12-0129111710.1186/s12929-022-00888-xPeriostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-β2 signalingSheng-Chieh Lin0Yi-Chu Liao1Po-Ming Chen2Ya-Yu Yang3Yi-Hsiang Wang4Shiao-Lin Tung5Chi-Mu Chuang6Yu-Wen Sung7Te-Hsuan Jang8Shuang-En Chuang9Lu-Hai Wang10Graduate Institute of Integrated Medicine and Chinese Medicine Research Center, China Medical UniversityInstitute of Molecular and Genomic Medicine, National Health Research InstitutesGraduate Institute of Integrated Medicine and Chinese Medicine Research Center, China Medical UniversityNational Institute of Cancer Research, National Health Research InstitutesInstitute of Molecular and Genomic Medicine, National Health Research InstitutesDepartment of Hematology and Oncology, Ton-Yen General HospitalDepartment of Obstetrics and Gynecology, Taipei Veterans General HospitalGraduate Institute of Biomedical Sciences, China Medical UniversityNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesGraduate Institute of Integrated Medicine and Chinese Medicine Research Center, China Medical UniversityAbstract Background Ovarian cancer has the highest mortality among gynecological cancers due to late diagnosis and lack of effective targeted therapy. Although the study of interplay between cancer cells with their microenvironment is emerging, how ovarian cancer triggers signaling that coordinates with immune cells to promote metastasis is still elusive. Methods Microarray and bioinformatics analysis of low and highly invasive ovarian cancer cell lines were used to reveal periostin (POSTN), a matrix protein with multifunctions in cancer, with elevated expression in the highly invasive cells. Anchorage independent assay, Western blot, RNA interference, confocal analysis and neutralizing antibody treatment were performed to analyze the effects of POSTN on tumor promotion and to explore the underlying mechanism. Chemotaxis, flow cytometry and cytokine array analyses were undertaken to analyze the involvement of POSTN in cancer-associated fibroblast (CAF) and macrophage modulation. Correlations between POSTN expression levels and clinical characteristics were analyzed using the Oncomine, commercial ovarian cancer cDNA and China Medical University Hospital patient cohort. In vivo effect of POSTN on metastasis was studied using a mouse xenograft model. Results Expression of POSTN was found to be elevated in highly invasive ovarian cancer cells. We observed that POSTN was co-localized with integrin β3 and integrin β5, which was important for POSTN-mediated activation of ERK and NF-κB. Ectopic expression of POSTN enhanced whereas knockdown of POSTN decreased cancer cell migration and invasion in vitro, as well as tumor growth and metastasis in vivo. POSTN enhanced integrin/ERK/NF-κB signaling through an autocrine effect on cancer cells to produce macrophage attracting and mobilizing cytokines including MIP-1β, MCP-1, TNFα and RANTES resulting in increased chemotaxis of THP-1 monocytes and their polarization to M2 macrophages in vitro. In agreement, tumors derived from POSTN-overexpressing SKOV3 harbored more tumor-associated macrophages than the control tumors. POSTN induced TGF-β2 expression from ovarian cancer cells to promote activation of adipose-derived stromal cells to become CAF-like cells expressing alpha smooth muscle actin and fibroblast activation protein alpha. Consistently, increased CAFs were observed in POSTN overexpressing SKOV3 cells-derived metastatic tumors. In clinical relevance, we found that expression of POSTN was positively correlated with advanced-stage diseases and poor overall survival of patients. Conclusions Our study revealed a POSTN-integrin-NF-κB-mediated signaling and its involvement in enhancing M2 macrophages and CAFs, which could potentially participate in promoting tumor growth. Our results suggest that POSTN could be a useful prognosis marker and potential therapeutic target.https://doi.org/10.1186/s12929-022-00888-xOvarian cancerMetastasisPeriostinMacrophagesCancer-associated fibroblastNF-κB |
| spellingShingle | Sheng-Chieh Lin Yi-Chu Liao Po-Ming Chen Ya-Yu Yang Yi-Hsiang Wang Shiao-Lin Tung Chi-Mu Chuang Yu-Wen Sung Te-Hsuan Jang Shuang-En Chuang Lu-Hai Wang Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-β2 signaling Journal of Biomedical Science Ovarian cancer Metastasis Periostin Macrophages Cancer-associated fibroblast NF-κB |
| title | Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-β2 signaling |
| title_full | Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-β2 signaling |
| title_fullStr | Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-β2 signaling |
| title_full_unstemmed | Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-β2 signaling |
| title_short | Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-β2 signaling |
| title_sort | periostin promotes ovarian cancer metastasis by enhancing m2 macrophages and cancer associated fibroblasts via integrin mediated nf κb and tgf β2 signaling |
| topic | Ovarian cancer Metastasis Periostin Macrophages Cancer-associated fibroblast NF-κB |
| url | https://doi.org/10.1186/s12929-022-00888-x |
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