Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma
Abstract Background Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-11-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02893-w |
| _version_ | 1797451037660938240 |
|---|---|
| author | Lingyun Zhou Linye He Chang-Hai Liu Huandi Qiu Li Zheng Klarke Michael Sample Qin Wu Jiaxin Li Kunlin Xie Javier Ampuero Zhihui Li Duoduo Lv Miao Liu Manuel Romero-Gómez Yiguo Hu Hong Tang |
| author_facet | Lingyun Zhou Linye He Chang-Hai Liu Huandi Qiu Li Zheng Klarke Michael Sample Qin Wu Jiaxin Li Kunlin Xie Javier Ampuero Zhihui Li Duoduo Lv Miao Liu Manuel Romero-Gómez Yiguo Hu Hong Tang |
| author_sort | Lingyun Zhou |
| collection | DOAJ |
| description | Abstract Background Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail. Methods 117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells. Results Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated β-catenin signaling pathway in LCSCs. Conclusions LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis. |
| first_indexed | 2024-03-09T14:49:10Z |
| format | Article |
| id | doaj.art-3ee30e25a973421c9596444d1bbe194d |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-09T14:49:10Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-3ee30e25a973421c9596444d1bbe194d2023-11-26T14:34:33ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-11-0142112510.1186/s13046-023-02893-wLiver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinomaLingyun Zhou0Linye He1Chang-Hai Liu2Huandi Qiu3Li Zheng4Klarke Michael Sample5Qin Wu6Jiaxin Li7Kunlin Xie8Javier Ampuero9Zhihui Li10Duoduo Lv11Miao Liu12Manuel Romero-Gómez13Yiguo Hu14Hong Tang15Center of Infectious Diseases, West China Hospital of Sichuan UniversityThyroid and Parathyroid Surgery Center, West China Hospital of Sichuan UniversityCenter of Infectious Diseases, West China Hospital of Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan UniversityCenter of Infectious Diseases, West China Hospital of Sichuan UniversityDepartment of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan UniversityDepartment of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan UniversityDigestive Diseases Unit, Virgen del Rocío University Hospital, SeLiver Group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US), University of SevilleThyroid and Parathyroid Surgery Center, West China Hospital of Sichuan UniversityCenter of Infectious Diseases, West China Hospital of Sichuan UniversityCenter of Infectious Diseases, West China Hospital of Sichuan UniversityDigestive Diseases Unit, Virgen del Rocío University Hospital, SeLiver Group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US), University of SevilleThyroid and Parathyroid Surgery Center, West China Hospital of Sichuan UniversityCenter of Infectious Diseases, West China Hospital of Sichuan UniversityAbstract Background Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail. Methods 117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells. Results Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated β-catenin signaling pathway in LCSCs. Conclusions LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis.https://doi.org/10.1186/s13046-023-02893-wLiver cancer stem cells (LCSCs)Hepatocellular carcinoma (HCC)MetastasisNRCAMSingle-cell RNA sequencingEpithelial-mesenchymal transition (EMT) |
| spellingShingle | Lingyun Zhou Linye He Chang-Hai Liu Huandi Qiu Li Zheng Klarke Michael Sample Qin Wu Jiaxin Li Kunlin Xie Javier Ampuero Zhihui Li Duoduo Lv Miao Liu Manuel Romero-Gómez Yiguo Hu Hong Tang Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma Journal of Experimental & Clinical Cancer Research Liver cancer stem cells (LCSCs) Hepatocellular carcinoma (HCC) Metastasis NRCAM Single-cell RNA sequencing Epithelial-mesenchymal transition (EMT) |
| title | Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma |
| title_full | Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma |
| title_fullStr | Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma |
| title_full_unstemmed | Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma |
| title_short | Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma |
| title_sort | liver cancer stem cell dissemination and metastasis uncovering the role of nrcam in hepatocellular carcinoma |
| topic | Liver cancer stem cells (LCSCs) Hepatocellular carcinoma (HCC) Metastasis NRCAM Single-cell RNA sequencing Epithelial-mesenchymal transition (EMT) |
| url | https://doi.org/10.1186/s13046-023-02893-w |
| work_keys_str_mv | AT lingyunzhou livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT linyehe livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT changhailiu livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT huandiqiu livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT lizheng livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT klarkemichaelsample livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT qinwu livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT jiaxinli livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT kunlinxie livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT javierampuero livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT zhihuili livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT duoduolv livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT miaoliu livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT manuelromerogomez livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT yiguohu livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma AT hongtang livercancerstemcelldisseminationandmetastasisuncoveringtheroleofnrcaminhepatocellularcarcinoma |