TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3
Abstract Background Tandem C2 domains, nuclear (TC2N) is a protein that has been characterized to contain C2A domain, C2B domain, and a short C-terminus with a WHXL motif. In previous studies, we have uncovered the oncogenic role and mechanisms of TC2N in lung cancer: TC2N achieves this by inhibitin...
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BMC
2025-01-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-025-01348-3 |
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| author | Jing Gu Yang-fan Lv Ji-ying Xia Fu-hai Bai Ji Gong Guang-qiang Pan Bo Liu Lu Huang Qiao-nan Guo Xiang-lin Hao |
| author_facet | Jing Gu Yang-fan Lv Ji-ying Xia Fu-hai Bai Ji Gong Guang-qiang Pan Bo Liu Lu Huang Qiao-nan Guo Xiang-lin Hao |
| author_sort | Jing Gu |
| collection | DOAJ |
| description | Abstract Background Tandem C2 domains, nuclear (TC2N) is a protein that has been characterized to contain C2A domain, C2B domain, and a short C-terminus with a WHXL motif. In previous studies, we have uncovered the oncogenic role and mechanisms of TC2N in lung cancer: TC2N achieves this by inhibiting the p53 signaling pathway and activating the NF-kappaB signaling pathway. Beyond that, its precise function in tumorigenesis is not fully understood. Methods TC2N-engineered mice model was used to assess the effect of TC2N knockout on normal lung and urethane-induced carcinogenesis. Tumor tissues of 395 lung cancer patients were subjected to tissue microarray and further assessed the associations of TC2N expression with tumor differentiation degree. The protein levels of TC2N and stem cell markers in cell lines and tissue specimens were monitored by WB and immunohistochemistry. In vitro cell assays were performed to assess the effect of TC2N ectopic expression on the stem cell-like characteristics of lung cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics and proteomics, and the underlying mechanism was explored by WB and co-IP assays. Results Herein, TC2N appeared to have a strong effect in promoting lung tumorigenesis caused by urethane, whereas it seemed to lose its function in the normal lung. Meanwhile, we found that the functional differences of TC2N between lung tumor and normal lung were linked to its potential role in cancer cell stemness. Function-wise, TC2N overexpression maintained stem-like properties of lung cancer cell. Mechanism-wise, TC2N upregulated the phosphorylation of EGFR, ERK, STAT3 and FAK1 to activate these signaling pathways by the inhibition of DUSP3 phosphatase via a dual mechanism. Firstly, TC2N competes with EGFR, ERK, STAT3 and FAK1 for binding to DUSP3. This competition prevents these signaling molecules from being dephosphorylated by DUSP3, resulting in their sustained activation. Secondly, TC2N bind to DUSP3 and restrict the enzyme’s ability to dephosphorylate the signaling molecules. Conclusions Overall, this study revealed a previously unknown role and mechanism of TC2N in the regulation of tumorigenesis and stemness in lung cancer cells. |
| format | Article |
| id | doaj-art-43c0a0df50644b7ba771566e22ddc8c9 |
| institution | Kabale University |
| issn | 2045-3701 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Cell & Bioscience |
| spelling | doaj-art-43c0a0df50644b7ba771566e22ddc8c92025-01-26T12:54:19ZengBMCCell & Bioscience2045-37012025-01-0115111910.1186/s13578-025-01348-3TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3Jing Gu0Yang-fan Lv1Ji-ying Xia2Fu-hai Bai3Ji Gong4Guang-qiang Pan5Bo Liu6Lu Huang7Qiao-nan Guo8Xiang-lin Hao9Institute of Toxicology, College of Preventive Medicine, Third Military Medical UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityDepartment of Anesthesiology, Xinqiao Hospital, Third Military Medical UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityDepartment of Pathology, Xinqiao Hospital, Third Military Medical UniversityAbstract Background Tandem C2 domains, nuclear (TC2N) is a protein that has been characterized to contain C2A domain, C2B domain, and a short C-terminus with a WHXL motif. In previous studies, we have uncovered the oncogenic role and mechanisms of TC2N in lung cancer: TC2N achieves this by inhibiting the p53 signaling pathway and activating the NF-kappaB signaling pathway. Beyond that, its precise function in tumorigenesis is not fully understood. Methods TC2N-engineered mice model was used to assess the effect of TC2N knockout on normal lung and urethane-induced carcinogenesis. Tumor tissues of 395 lung cancer patients were subjected to tissue microarray and further assessed the associations of TC2N expression with tumor differentiation degree. The protein levels of TC2N and stem cell markers in cell lines and tissue specimens were monitored by WB and immunohistochemistry. In vitro cell assays were performed to assess the effect of TC2N ectopic expression on the stem cell-like characteristics of lung cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics and proteomics, and the underlying mechanism was explored by WB and co-IP assays. Results Herein, TC2N appeared to have a strong effect in promoting lung tumorigenesis caused by urethane, whereas it seemed to lose its function in the normal lung. Meanwhile, we found that the functional differences of TC2N between lung tumor and normal lung were linked to its potential role in cancer cell stemness. Function-wise, TC2N overexpression maintained stem-like properties of lung cancer cell. Mechanism-wise, TC2N upregulated the phosphorylation of EGFR, ERK, STAT3 and FAK1 to activate these signaling pathways by the inhibition of DUSP3 phosphatase via a dual mechanism. Firstly, TC2N competes with EGFR, ERK, STAT3 and FAK1 for binding to DUSP3. This competition prevents these signaling molecules from being dephosphorylated by DUSP3, resulting in their sustained activation. Secondly, TC2N bind to DUSP3 and restrict the enzyme’s ability to dephosphorylate the signaling molecules. Conclusions Overall, this study revealed a previously unknown role and mechanism of TC2N in the regulation of tumorigenesis and stemness in lung cancer cells.https://doi.org/10.1186/s13578-025-01348-3TC2NLung cancerDUSP3 phosphataseUrethaneTumorigenesisStemness |
| spellingShingle | Jing Gu Yang-fan Lv Ji-ying Xia Fu-hai Bai Ji Gong Guang-qiang Pan Bo Liu Lu Huang Qiao-nan Guo Xiang-lin Hao TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3 Cell & Bioscience TC2N Lung cancer DUSP3 phosphatase Urethane Tumorigenesis Stemness |
| title | TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3 |
| title_full | TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3 |
| title_fullStr | TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3 |
| title_full_unstemmed | TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3 |
| title_short | TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3 |
| title_sort | tc2n maintains stem cell like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3 |
| topic | TC2N Lung cancer DUSP3 phosphatase Urethane Tumorigenesis Stemness |
| url | https://doi.org/10.1186/s13578-025-01348-3 |
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