IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathway
Abstract Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. The disease recurrent rate is relatively high resulted in poor 5-year survival in advanced HCC. Cancer stem cells (CSCs) have been considered to be one of the main mechanisms for chemore...
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| Format: | Article |
| Language: | English |
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BMC
2018-05-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-018-4529-9 |
| _version_ | 1818864451584000000 |
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| author | Wei-Chieh Huang Shiao-Lin Tung Yao-Li Chen Po-Ming Chen Pei-Yi Chu |
| author_facet | Wei-Chieh Huang Shiao-Lin Tung Yao-Li Chen Po-Ming Chen Pei-Yi Chu |
| author_sort | Wei-Chieh Huang |
| collection | DOAJ |
| description | Abstract Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. The disease recurrent rate is relatively high resulted in poor 5-year survival in advanced HCC. Cancer stem cells (CSCs) have been considered to be one of the main mechanisms for chemoresistance, metastasis, and recurrent disease. Interferon-induced protein 44-like (IFI44L) gene is a type I interferon-stimulated gene (ISG) and belongs to the IFI44 family. Previous reports indicated antiviral activity against HCV in IFI44L, however, its precise role and function in HCC has not been unveiled. Methods To explore the characteristics of hepatic CSCs, we successfully enriched hepatic cancer stem-like cells from three established liver cancer cell lines (Hep3B, HepG2, and PLC lines). Parental Hep3B and HepG2 cells and their sphere cells were treated with doxorubicin for 48 h and cell viability was measured by MTT assay. HCC tissue blocks from 217 patients were sampled for tissue microarray (TMA). Follow-up information and histopathological and clinical data including age, gender, tumor grade, advanced stages, HBV, HCV, tumor number, tumor size, relapse-free survival, and overall survival were obtained from the cancer registry and medical charts. The liver TMA was evaluated for IFI44L expression using immunohistochemical staining and scores. Results These hepatic cancer stem-like cells possess important cancer stemness characteristics including sphere-forming abilities, expressing important HCC cancer stem cell markers, and more chemoresistant. Interestingly, we found that overexpression of IFI44L decreased chemoresistance towards doxorubicin and knockdown of IFI44L restored chemoresistance as well as promoted sphere formation. Furthermore, we found that depletion of IFI44L enhanced migration, invasion, and pulmonary metastasis through activating Met/Src signaling pathway. Clinically, the expression level of IFI44L significantly reduced in HCC tumor tissues. Low expression of IFI44L levels also correlated with larger tumor size, disease relapse, advanced stages, and poor clinical survival in HCC patients. Conclusion Taken together, we first demonstrated that IFI44L is a novel tumor suppressor to affect cancer stemness, metastasis, and drug resistance via regulating Met/Src signaling pathway in HCC and can be serve as an important prognostic marker. |
| first_indexed | 2024-12-19T10:31:52Z |
| format | Article |
| id | doaj.art-bbe5d679c8c2422288b55f07ded65ded |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-19T10:31:52Z |
| publishDate | 2018-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-bbe5d679c8c2422288b55f07ded65ded2022-12-21T20:25:44ZengBMCBMC Cancer1471-24072018-05-0118111010.1186/s12885-018-4529-9IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathwayWei-Chieh Huang0Shiao-Lin Tung1Yao-Li Chen2Po-Ming Chen3Pei-Yi Chu4Graduate Institute of Integrated Medicine, China Medical UniversityDepartment of Hematology and Oncology, Ton-Yen General HospitalSchool of Medicine, Kaohsiung Medical UniversityTaiwan Agricultural Chemicals and Toxic Substances Research Institute, Council of AgricultureSchool of Medicine, College of Medicine, Fu Jen Catholic UniversityAbstract Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. The disease recurrent rate is relatively high resulted in poor 5-year survival in advanced HCC. Cancer stem cells (CSCs) have been considered to be one of the main mechanisms for chemoresistance, metastasis, and recurrent disease. Interferon-induced protein 44-like (IFI44L) gene is a type I interferon-stimulated gene (ISG) and belongs to the IFI44 family. Previous reports indicated antiviral activity against HCV in IFI44L, however, its precise role and function in HCC has not been unveiled. Methods To explore the characteristics of hepatic CSCs, we successfully enriched hepatic cancer stem-like cells from three established liver cancer cell lines (Hep3B, HepG2, and PLC lines). Parental Hep3B and HepG2 cells and their sphere cells were treated with doxorubicin for 48 h and cell viability was measured by MTT assay. HCC tissue blocks from 217 patients were sampled for tissue microarray (TMA). Follow-up information and histopathological and clinical data including age, gender, tumor grade, advanced stages, HBV, HCV, tumor number, tumor size, relapse-free survival, and overall survival were obtained from the cancer registry and medical charts. The liver TMA was evaluated for IFI44L expression using immunohistochemical staining and scores. Results These hepatic cancer stem-like cells possess important cancer stemness characteristics including sphere-forming abilities, expressing important HCC cancer stem cell markers, and more chemoresistant. Interestingly, we found that overexpression of IFI44L decreased chemoresistance towards doxorubicin and knockdown of IFI44L restored chemoresistance as well as promoted sphere formation. Furthermore, we found that depletion of IFI44L enhanced migration, invasion, and pulmonary metastasis through activating Met/Src signaling pathway. Clinically, the expression level of IFI44L significantly reduced in HCC tumor tissues. Low expression of IFI44L levels also correlated with larger tumor size, disease relapse, advanced stages, and poor clinical survival in HCC patients. Conclusion Taken together, we first demonstrated that IFI44L is a novel tumor suppressor to affect cancer stemness, metastasis, and drug resistance via regulating Met/Src signaling pathway in HCC and can be serve as an important prognostic marker.http://link.springer.com/article/10.1186/s12885-018-4529-9IFI44LCancer stem cellsHepatocellular carcinoma |
| spellingShingle | Wei-Chieh Huang Shiao-Lin Tung Yao-Li Chen Po-Ming Chen Pei-Yi Chu IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathway BMC Cancer IFI44L Cancer stem cells Hepatocellular carcinoma |
| title | IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathway |
| title_full | IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathway |
| title_fullStr | IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathway |
| title_full_unstemmed | IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathway |
| title_short | IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathway |
| title_sort | ifi44l is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness metastasis and drug resistance via regulating met src signaling pathway |
| topic | IFI44L Cancer stem cells Hepatocellular carcinoma |
| url | http://link.springer.com/article/10.1186/s12885-018-4529-9 |
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