PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer
Abstract Background Par-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis. Methods The essential role of PARD3 in mediating hepatic tumorigenesis was assesse...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-02-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-024-02967-3 |
| _version_ | 1827325743254732800 |
|---|---|
| author | Junyu Wu Hor-Yue Tan Yau-Tuen Chan Yuanjun Lu Zixin Feng Hongchao Yuan Cheng Zhang Yibin Feng Ning Wang |
| author_facet | Junyu Wu Hor-Yue Tan Yau-Tuen Chan Yuanjun Lu Zixin Feng Hongchao Yuan Cheng Zhang Yibin Feng Ning Wang |
| author_sort | Junyu Wu |
| collection | DOAJ |
| description | Abstract Background Par-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis. Methods The essential role of PARD3 in mediating hepatic tumorigenesis was assessed in diet-induced spontaneous liver tumour and syngeneic tumour models. The mechanism of PARD3 was delineated by bulk and single-cell RNA sequencing. The clinical significance of PARD3 was identified by tissue array analysis. Results PARD3 was overexpressed in tumour tissues and PARD3 overexpression was positively correlated with high tumour stage as well as the poor prognosis in patients. In models of spontaneous liver cancer induced by choline-deficient, amino acid-defined (CDAA) and methionine-choline-deficient (MCD) diets, upregulation of PARD3 was induced specifically at the tumorigenesis stage rather than other early stages of liver disease progression. Site-directed knockout of PARD3 using an adeno-associated virus 8 (AAV8)-delivered CRISPR/Cas9 single-guide RNA (sgRNA) plasmid blocked hepatic tumorigenesis, while PARD3 overexpression accelerated liver tumour progression. In particular, single-cell sequencing analysis suggested that PARD3 was enriched in primitive tumour cells and its overexpression enhanced tumour-initiating cell (TICs). Overexpression of PARD3 maintained the self-renewal ability of the CD133+ TIC population within hepatocellular carcinoma (HCC) cells and promoted the in vitro and in vivo tumorigenicity of CD133+ TICs. Transcriptome analysis revealed that Sonic Hedgehog (SHH) signalling was activated in PARD3-overexpressing CD133+ TICs. Mechanistically, PARD3 interacted with aPKC to further activate SHH signalling and downstream stemness-related genes. Suppression of SHH signalling and aPKC expression attenuated the in vitro and in vivo tumorigenicity of PARD3-overexpressing CD133+ TICs. Tissue array analysis revealed that PARD3 expression was positively associated with the phosphorylation of aPKC, SOX2 and Gli1 and that the combination of these markers could be used to stratify HCC patients into two clusters with different clinicopathological characteristics and overall survival prognoses. The natural compound berberine was selected as a potent suppressor of PARD3 expression and could be used as a preventive agent for liver cancer that completely blocks diet-induced hepatic tumorigenesis in a PARD3-dependent manner. Conclusion This study revealed PARD3 as a potential preventive target of liver tumorigenesis via TIC regulation. |
| first_indexed | 2024-03-07T14:34:35Z |
| format | Article |
| id | doaj.art-30e5f01326084773a84fb32e1af2100b |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-07T14:34:35Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-30e5f01326084773a84fb32e1af2100b2024-03-05T20:43:36ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-02-0143111710.1186/s13046-024-02967-3PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancerJunyu Wu0Hor-Yue Tan1Yau-Tuen Chan2Yuanjun Lu3Zixin Feng4Hongchao Yuan5Cheng Zhang6Yibin Feng7Ning Wang8School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Chinese Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Chinese Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Chinese Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Chinese Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Chinese Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Chinese Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Chinese Medicine, LKS Faculty of Medicine, The University of Hong KongSchool of Chinese Medicine, LKS Faculty of Medicine, The University of Hong KongAbstract Background Par-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis. Methods The essential role of PARD3 in mediating hepatic tumorigenesis was assessed in diet-induced spontaneous liver tumour and syngeneic tumour models. The mechanism of PARD3 was delineated by bulk and single-cell RNA sequencing. The clinical significance of PARD3 was identified by tissue array analysis. Results PARD3 was overexpressed in tumour tissues and PARD3 overexpression was positively correlated with high tumour stage as well as the poor prognosis in patients. In models of spontaneous liver cancer induced by choline-deficient, amino acid-defined (CDAA) and methionine-choline-deficient (MCD) diets, upregulation of PARD3 was induced specifically at the tumorigenesis stage rather than other early stages of liver disease progression. Site-directed knockout of PARD3 using an adeno-associated virus 8 (AAV8)-delivered CRISPR/Cas9 single-guide RNA (sgRNA) plasmid blocked hepatic tumorigenesis, while PARD3 overexpression accelerated liver tumour progression. In particular, single-cell sequencing analysis suggested that PARD3 was enriched in primitive tumour cells and its overexpression enhanced tumour-initiating cell (TICs). Overexpression of PARD3 maintained the self-renewal ability of the CD133+ TIC population within hepatocellular carcinoma (HCC) cells and promoted the in vitro and in vivo tumorigenicity of CD133+ TICs. Transcriptome analysis revealed that Sonic Hedgehog (SHH) signalling was activated in PARD3-overexpressing CD133+ TICs. Mechanistically, PARD3 interacted with aPKC to further activate SHH signalling and downstream stemness-related genes. Suppression of SHH signalling and aPKC expression attenuated the in vitro and in vivo tumorigenicity of PARD3-overexpressing CD133+ TICs. Tissue array analysis revealed that PARD3 expression was positively associated with the phosphorylation of aPKC, SOX2 and Gli1 and that the combination of these markers could be used to stratify HCC patients into two clusters with different clinicopathological characteristics and overall survival prognoses. The natural compound berberine was selected as a potent suppressor of PARD3 expression and could be used as a preventive agent for liver cancer that completely blocks diet-induced hepatic tumorigenesis in a PARD3-dependent manner. Conclusion This study revealed PARD3 as a potential preventive target of liver tumorigenesis via TIC regulation.https://doi.org/10.1186/s13046-024-02967-3PARD3Hepatic tumorigenesisCancer stem cellsSonic hedgehogBerberine |
| spellingShingle | Junyu Wu Hor-Yue Tan Yau-Tuen Chan Yuanjun Lu Zixin Feng Hongchao Yuan Cheng Zhang Yibin Feng Ning Wang PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer Journal of Experimental & Clinical Cancer Research PARD3 Hepatic tumorigenesis Cancer stem cells Sonic hedgehog Berberine |
| title | PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer |
| title_full | PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer |
| title_fullStr | PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer |
| title_full_unstemmed | PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer |
| title_short | PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer |
| title_sort | pard3 drives tumorigenesis through activating sonic hedgehog signalling in tumour initiating cells in liver cancer |
| topic | PARD3 Hepatic tumorigenesis Cancer stem cells Sonic hedgehog Berberine |
| url | https://doi.org/10.1186/s13046-024-02967-3 |
| work_keys_str_mv | AT junyuwu pard3drivestumorigenesisthroughactivatingsonichedgehogsignallingintumourinitiatingcellsinlivercancer AT horyuetan pard3drivestumorigenesisthroughactivatingsonichedgehogsignallingintumourinitiatingcellsinlivercancer AT yautuenchan pard3drivestumorigenesisthroughactivatingsonichedgehogsignallingintumourinitiatingcellsinlivercancer AT yuanjunlu pard3drivestumorigenesisthroughactivatingsonichedgehogsignallingintumourinitiatingcellsinlivercancer AT zixinfeng pard3drivestumorigenesisthroughactivatingsonichedgehogsignallingintumourinitiatingcellsinlivercancer AT hongchaoyuan pard3drivestumorigenesisthroughactivatingsonichedgehogsignallingintumourinitiatingcellsinlivercancer AT chengzhang pard3drivestumorigenesisthroughactivatingsonichedgehogsignallingintumourinitiatingcellsinlivercancer AT yibinfeng pard3drivestumorigenesisthroughactivatingsonichedgehogsignallingintumourinitiatingcellsinlivercancer AT ningwang pard3drivestumorigenesisthroughactivatingsonichedgehogsignallingintumourinitiatingcellsinlivercancer |