Sema3d Restrained Hepatocellular Carcinoma Progression Through Inactivating Pi3k/Akt Signaling via Interaction With FLNA
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide due to the high incidence rate of metastasis and recurrence. Semaphorin 3d (Sema3d) has been shown to play a critical role in vascular development during early embryogenesis and several forms of cancer progression vi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.913498/full |
| _version_ | 1828785268915699712 |
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| author | Yiming Li Cong Xu Bo Sun Fangjing Zhong Momo Cao Lianyue Yang |
| author_facet | Yiming Li Cong Xu Bo Sun Fangjing Zhong Momo Cao Lianyue Yang |
| author_sort | Yiming Li |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide due to the high incidence rate of metastasis and recurrence. Semaphorin 3d (Sema3d) has been shown to play a critical role in vascular development during early embryogenesis and several forms of cancer progression via regulating cell migration. However, the function of Sema3d in hepatocellular carcinoma (HCC) remains elusive. This study aimed to explore the function and mechanisms of Sema3d in HCC. In our study, Sema3d expression was significantly downregulated in HCC tissues and cell lines. Downregulated Sema3d was closely correlated with aggressive clinicopathological features and poor clinical outcomes in HCC patients. Moreover, overexpression of Sema3d in HCCLM3 cells was significantly inhibited and knockdown of Sema3d in PLC/PRF/5 cells promoted proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of HCC cells in vitro and tumor growth, EMT, and metastasis in vivo. Furthermore, the RNA sequencing and gene set enrichment analysis (GSEA) indicated that these phenotypic and functional changes in Sema3d-interfered HCC cells were mediated by the Pi3k/Akt signaling pathway, and co-IP–combined mass spectrometry indicated Sema3d might interact with FLNA. Finally, we proved that Sema3d exerted its tumor-restraining effect by interacting with FLNA to inactivate the Pi3k/Akt signaling pathway and remodel the cytoskeleton. Our data showed that Sema3d restrained hepatocellular carcinoma proliferation, invasion, and metastasis through inactivating Pi3k/Akt via interaction with FLNA, which may serve as a novel prognostic predictor and a potential therapeutic target for HCC patients. |
| first_indexed | 2024-12-11T23:47:53Z |
| format | Article |
| id | doaj.art-4ce1016b88f94910996cb1f2673fabf1 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-11T23:47:53Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-4ce1016b88f94910996cb1f2673fabf12022-12-22T00:45:34ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-07-011210.3389/fonc.2022.913498913498Sema3d Restrained Hepatocellular Carcinoma Progression Through Inactivating Pi3k/Akt Signaling via Interaction With FLNAYiming LiCong XuBo SunFangjing ZhongMomo CaoLianyue YangHepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide due to the high incidence rate of metastasis and recurrence. Semaphorin 3d (Sema3d) has been shown to play a critical role in vascular development during early embryogenesis and several forms of cancer progression via regulating cell migration. However, the function of Sema3d in hepatocellular carcinoma (HCC) remains elusive. This study aimed to explore the function and mechanisms of Sema3d in HCC. In our study, Sema3d expression was significantly downregulated in HCC tissues and cell lines. Downregulated Sema3d was closely correlated with aggressive clinicopathological features and poor clinical outcomes in HCC patients. Moreover, overexpression of Sema3d in HCCLM3 cells was significantly inhibited and knockdown of Sema3d in PLC/PRF/5 cells promoted proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of HCC cells in vitro and tumor growth, EMT, and metastasis in vivo. Furthermore, the RNA sequencing and gene set enrichment analysis (GSEA) indicated that these phenotypic and functional changes in Sema3d-interfered HCC cells were mediated by the Pi3k/Akt signaling pathway, and co-IP–combined mass spectrometry indicated Sema3d might interact with FLNA. Finally, we proved that Sema3d exerted its tumor-restraining effect by interacting with FLNA to inactivate the Pi3k/Akt signaling pathway and remodel the cytoskeleton. Our data showed that Sema3d restrained hepatocellular carcinoma proliferation, invasion, and metastasis through inactivating Pi3k/Akt via interaction with FLNA, which may serve as a novel prognostic predictor and a potential therapeutic target for HCC patients.https://www.frontiersin.org/articles/10.3389/fonc.2022.913498/fullSema3dsemaphorin 3dhepatocellular carcinomaprognosiscancer progressionPi3k/Akt signaling |
| spellingShingle | Yiming Li Cong Xu Bo Sun Fangjing Zhong Momo Cao Lianyue Yang Sema3d Restrained Hepatocellular Carcinoma Progression Through Inactivating Pi3k/Akt Signaling via Interaction With FLNA Frontiers in Oncology Sema3d semaphorin 3d hepatocellular carcinoma prognosis cancer progression Pi3k/Akt signaling |
| title | Sema3d Restrained Hepatocellular Carcinoma Progression Through Inactivating Pi3k/Akt Signaling via Interaction With FLNA |
| title_full | Sema3d Restrained Hepatocellular Carcinoma Progression Through Inactivating Pi3k/Akt Signaling via Interaction With FLNA |
| title_fullStr | Sema3d Restrained Hepatocellular Carcinoma Progression Through Inactivating Pi3k/Akt Signaling via Interaction With FLNA |
| title_full_unstemmed | Sema3d Restrained Hepatocellular Carcinoma Progression Through Inactivating Pi3k/Akt Signaling via Interaction With FLNA |
| title_short | Sema3d Restrained Hepatocellular Carcinoma Progression Through Inactivating Pi3k/Akt Signaling via Interaction With FLNA |
| title_sort | sema3d restrained hepatocellular carcinoma progression through inactivating pi3k akt signaling via interaction with flna |
| topic | Sema3d semaphorin 3d hepatocellular carcinoma prognosis cancer progression Pi3k/Akt signaling |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.913498/full |
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