A Novel 167‐Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα Ubiquitination
Abstract Intrahepatic cholangiocarcinoma (ICC), a formidable challenge in oncology, demands innovative biomarkers and therapeutic targets. This research highlights the importance of the circular RNA (circRNA) circPCSK6 and its peptide derivative circPCSK6‐167aa in ICC. CircPCSK6 is significantly dow...
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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202409173 |
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| author | Canghai Guan Jianjun Gao Xinlei Zou Wujiang Shi Yunhe Hao Yifei Ge Zhaoqiang Xu Chengru Yang Shaowu Bi Xingming Jiang Pengcheng Kang Xiaoxue Xu Xiangyu Zhong |
| author_facet | Canghai Guan Jianjun Gao Xinlei Zou Wujiang Shi Yunhe Hao Yifei Ge Zhaoqiang Xu Chengru Yang Shaowu Bi Xingming Jiang Pengcheng Kang Xiaoxue Xu Xiangyu Zhong |
| author_sort | Canghai Guan |
| collection | DOAJ |
| description | Abstract Intrahepatic cholangiocarcinoma (ICC), a formidable challenge in oncology, demands innovative biomarkers and therapeutic targets. This research highlights the importance of the circular RNA (circRNA) circPCSK6 and its peptide derivative circPCSK6‐167aa in ICC. CircPCSK6 is significantly downregulated in both ICC patients and mouse primary ICC models, and its lower expression is linked to adverse prognosis, highlighting its pivotal role in ICC pathogenesis. Functionally, this study elucidates the regulatory effect of circPCSK6‐167aa on IκBα ubiquitination within the NF‐κB pathway, which is mediated by its competitive binding to the E3 ligase RBBP6. This complex interaction leads to reduced activation of the NF‐κB pathway, thereby curbing tumor cell proliferation, migration, invasion, stemness, and hepatic‐lung metastasis in vivo. This groundbreaking discovery expands the understanding of circRNA‐driven tumorigenesis through atypical signaling pathways. Additionally, this investigation identified EIF4A3 as a detrimental regulator of circPCSK6, exacerbating ICC malignancy. Importantly, by leveraging patient‐derived xenograft (PDX), organoids, and organoid‐derived PDX models, higher levels of circPCSK6‐167aa enhance sensitivity to gemcitabine, indicating its potential to improve the effectiveness of chemotherapy. These insights emphasize the therapeutic promise of targeting circPCSK6‐167aa, offering vital biological insights and clinical directions for developing cutting‐edge therapeutic approaches, thus revealing innovative strategies and targets for future treatments. |
| format | Article |
| id | doaj-art-eda01abca1f645c9bf552e7f50bf607d |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-eda01abca1f645c9bf552e7f50bf607d2025-08-20T03:10:53ZengWileyAdvanced Science2198-38442025-03-011210n/an/a10.1002/advs.202409173A Novel 167‐Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα UbiquitinationCanghai Guan0Jianjun Gao1Xinlei Zou2Wujiang Shi3Yunhe Hao4Yifei Ge5Zhaoqiang Xu6Chengru Yang7Shaowu Bi8Xingming Jiang9Pengcheng Kang10Xiaoxue Xu11Xiangyu Zhong12General Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaSchool of Health Administration Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaGeneral Surgery Department The 2nd Affiliated Hospital of Harbin Medical University 148 Baojian Street Harbin Heilongjiang Province 150086 ChinaAbstract Intrahepatic cholangiocarcinoma (ICC), a formidable challenge in oncology, demands innovative biomarkers and therapeutic targets. This research highlights the importance of the circular RNA (circRNA) circPCSK6 and its peptide derivative circPCSK6‐167aa in ICC. CircPCSK6 is significantly downregulated in both ICC patients and mouse primary ICC models, and its lower expression is linked to adverse prognosis, highlighting its pivotal role in ICC pathogenesis. Functionally, this study elucidates the regulatory effect of circPCSK6‐167aa on IκBα ubiquitination within the NF‐κB pathway, which is mediated by its competitive binding to the E3 ligase RBBP6. This complex interaction leads to reduced activation of the NF‐κB pathway, thereby curbing tumor cell proliferation, migration, invasion, stemness, and hepatic‐lung metastasis in vivo. This groundbreaking discovery expands the understanding of circRNA‐driven tumorigenesis through atypical signaling pathways. Additionally, this investigation identified EIF4A3 as a detrimental regulator of circPCSK6, exacerbating ICC malignancy. Importantly, by leveraging patient‐derived xenograft (PDX), organoids, and organoid‐derived PDX models, higher levels of circPCSK6‐167aa enhance sensitivity to gemcitabine, indicating its potential to improve the effectiveness of chemotherapy. These insights emphasize the therapeutic promise of targeting circPCSK6‐167aa, offering vital biological insights and clinical directions for developing cutting‐edge therapeutic approaches, thus revealing innovative strategies and targets for future treatments.https://doi.org/10.1002/advs.202409173circCPSK6circular RNAintrahepatic cholangiocarcinomaNF‐κBubiquitination |
| spellingShingle | Canghai Guan Jianjun Gao Xinlei Zou Wujiang Shi Yunhe Hao Yifei Ge Zhaoqiang Xu Chengru Yang Shaowu Bi Xingming Jiang Pengcheng Kang Xiaoxue Xu Xiangyu Zhong A Novel 167‐Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα Ubiquitination Advanced Science circCPSK6 circular RNA intrahepatic cholangiocarcinoma NF‐κB ubiquitination |
| title | A Novel 167‐Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα Ubiquitination |
| title_full | A Novel 167‐Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα Ubiquitination |
| title_fullStr | A Novel 167‐Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα Ubiquitination |
| title_full_unstemmed | A Novel 167‐Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα Ubiquitination |
| title_short | A Novel 167‐Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα Ubiquitination |
| title_sort | novel 167 amino acid protein encoded by circpcsk6 inhibits intrahepatic cholangiocarcinoma progression via ikbα ubiquitination |
| topic | circCPSK6 circular RNA intrahepatic cholangiocarcinoma NF‐κB ubiquitination |
| url | https://doi.org/10.1002/advs.202409173 |
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