{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:10:40Z","timestamp":1755216640132,"version":"3.43.0"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32200110"],"award-info":[{"award-number":["32200110"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010023","name":"Natural Science Research of Jiangsu Higher Education Institutions of China","doi-asserted-by":"publisher","award":["22KJB230002"],"award-info":[{"award-number":["22KJB230002"]}],"id":[{"id":"10.13039\/501100010023","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Provincial-level talent program for National center of technologyinnovation for biopharmaceuticals","award":["NCTIB2024JS0101"],"award-info":[{"award-number":["NCTIB2024JS0101"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with difficult treatment and poor prognosis, whose pathogenesis could be associated with the expression patterns of circular RNAs (circRNAs). Here, we aim to investigate the effects and mechanism of hsa_circ_0006834 on iCCA proliferation. At first, hsa_circ_0006834 was proved to suppress iCCA cells proliferation and induce autophagy following the construction of hsa_circ_0006834 vector. And hsa_circ_0006834 is negatively linked with the proliferation, migration and invasion of iCCA cells through autophagy. Subsequently, RNA pull-down and dual-luciferase reporter assays were performed to validate the hsa_circ_0006834-has-miR-637-NGFR regulatory network. It was demonstrated by qPCR and Western blot that hsa_circ_0006834 stimulates the AMPK-mTOR pathway and triggers autophagy via NGFR after si-NGFR was synthesized and transfected into iCCA cells. Ultimately, after the successful knockdown of AMPK, the role of the AMPK-mTOR pathway in hsa_circ_0006834 regulating autophagy and proliferation was verified. Taken together, our findings revealed that hsa_circ_0006834 activates the AMPK-mTOR pathway and autophagy to suppress iCCA proliferation by has-miR-637-NGFR network, indicating the potential of hsa_circ_0006834 as a biomarker for iCCA diagnosis and therapy.<\/jats:p>","DOI":"10.1371\/journal.pone.0329847","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T17:35:13Z","timestamp":1754328913000},"page":"e0329847","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hsa_circ_0006834 represses intrahepatic cholangiocarcinoma proliferation through activating AMPK-mTOR pathway and autophagy via has-miR-637-NGFR network"],"prefix":"10.1371","volume":"20","author":[{"given":"Ji","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyue","family":"Qi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wangqian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyan","family":"Hao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kehan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuting","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunshan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"issue":"6","key":"pone.0329847.ref001","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.jhep.2014.01.021","article-title":"Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma","volume":"60","author":"J Bridgewater","year":"2014","journal-title":"Journal of Hepatology"},{"issue":"05","key":"pone.0329847.ref002","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1055\/s-0040-1719188","article-title":"Intrahepatic Cholangiocarcinoma","volume":"37","author":"P Entezari","year":"2020","journal-title":"Semin intervent Radiol"},{"issue":"2","key":"pone.0329847.ref003","first-page":"198","article-title":"Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and\u00a0future\u00a0therapeutic landscape for clinicians","volume":"73","author":"D Moris","year":"2023","journal-title":"CA Cancer J Clin"},{"issue":"1","key":"pone.0329847.ref004","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s12943-020-01286-3","article-title":"Circular RNA: metabolism, functions and interactions with proteins","volume":"19","author":"W-Y Zhou","year":"2020","journal-title":"Mol Cancer"},{"issue":"1","key":"pone.0329847.ref005","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41419-020-2230-9","article-title":"circRNA-002178 act as a ceRNA to promote PDL1\/PD1 expression in lung adenocarcinoma","volume":"11","author":"J Wang","year":"2020","journal-title":"Cell Death Dis"},{"issue":"4","key":"pone.0329847.ref006","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/s41419-022-04732-w","article-title":"Hsa_circRNA_0088036 acts as a ceRNA to promote bladder cancer progression by sponging miR-140-3p","volume":"13","author":"J Yang","year":"2022","journal-title":"Cell Death Dis"},{"issue":"4","key":"pone.0329847.ref007","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.7150\/thno.45302","article-title":"Estrogen-induced circRNA, circPGR, functions as a ceRNA to promote estrogen receptor-positive breast cancer cell growth by regulating cell cycle-related genes","volume":"11","author":"L Wang","year":"2021","journal-title":"Theranostics"},{"issue":"12","key":"pone.0329847.ref008","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.3390\/nu14122413","article-title":"Resveratrol Induces Autophagy and Apoptosis in Non-Small-Cell Lung Cancer Cells by Activating the NGFR-AMPK-mTOR Pathway","volume":"14","author":"J Li","year":"2022","journal-title":"Nutrients"},{"key":"pone.0329847.ref009","article-title":"NGFR Increases the Chemosensitivity of Colorectal Cancer Cells by Enhancing the Apoptotic and Autophagic Effects of 5-fluorouracil via the Activation of S100A9","volume":"11","author":"H Chen","year":"2021","journal-title":"Front Oncol"},{"key":"pone.0329847.ref010","doi-asserted-by":"crossref","DOI":"10.1038\/s41420-023-01631-7","article-title":"The role and implication of autophagy in cholangiocarcinoma","volume":"9","author":"H Khizar","year":"2023","journal-title":"Cell Death Discov"},{"issue":"3","key":"pone.0329847.ref011","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1053\/j.gastro.2022.11.025","article-title":"PTEN Deficiency Facilitates Exosome Secretion and Metastasis in Cholangiocarcinoma by Impairing TFEB-mediated Lysosome Biogenesis","volume":"164","author":"T-Y Jiang","year":"2023","journal-title":"Gastroenterology"},{"issue":"7","key":"pone.0329847.ref012","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1111\/liv.15904","article-title":"Neurokinin\u20101 receptor antagonist aprepitant regulates autophagy and apoptosis via ROS\/JNK in intrahepatic cholangiocarcinoma","volume":"44","author":"Y Yang","year":"2024","journal-title":"Liver International"},{"issue":"5","key":"pone.0329847.ref013","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1158\/0008-5472.CAN-21-2342","article-title":"AMPK\u2013mTOR\u2013Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells","volume":"82","author":"B You","year":"2022","journal-title":"Cancer Research"},{"issue":"1","key":"pone.0329847.ref014","doi-asserted-by":"crossref","first-page":"46","DOI":"10.5847\/wjem.j.1920-8642.2022.015","article-title":"Protective effect of mesenchymal stem cell-derived exosomal treatment of hippocampal neurons against oxygen-glucose deprivation\/reperfusion-induced injury","volume":"13","author":"X Guo","year":"2022","journal-title":"World Journal of Emergency Medicine"},{"key":"pone.0329847.ref015","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2022.942853","article-title":"The expression profiles of circular RNAs and competing endogenous RNA networks in intrahepatic cholangiocarcinoma","volume":"10","author":"Z Liang","year":"2022","journal-title":"Front Cell Dev Biol"},{"issue":"4","key":"pone.0329847.ref016","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: Renovation of Cells and Tissues","volume":"147","author":"N Mizushima","year":"2011","journal-title":"Cell"},{"issue":"7","key":"pone.0329847.ref017","doi-asserted-by":"crossref","first-page":"166400","DOI":"10.1016\/j.bbadis.2022.166400","article-title":"Role and regulation of autophagy in cancer","volume":"1868","author":"R Rakesh","year":"2022","journal-title":"Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease"},{"issue":"11","key":"pone.0329847.ref018","doi-asserted-by":"crossref","first-page":"6002","DOI":"10.3390\/ijms25116002","article-title":"The Diagnostic and Prognostic Potentials of Non-Coding RNA in Cholangiocarcinoma","volume":"25","author":"R Andrade","year":"2024","journal-title":"IJMS"},{"issue":"1","key":"pone.0329847.ref019","article-title":"CircNFIB inhibits tumor growth and metastasis through suppressing MEK1\/ERK signaling in intrahepatic cholangiocarcinoma","volume":"21","author":"J Du","year":"2022","journal-title":"Mol Cancer"},{"issue":"32","key":"pone.0329847.ref020","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202303814","article-title":"A Novel Trojan Horse Nanotherapy Strategy Targeting the cPKM\u2010STMN1\/TGFB1 Axis for Effective Treatment of Intrahepatic Cholangiocarcinoma","volume":"10","author":"Z Chen","year":"2023","journal-title":"Advanced Science"},{"issue":"7441","key":"pone.0329847.ref021","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature11928","article-title":"Circular RNAs are a large class of animal RNAs with regulatory potency","volume":"495","author":"S Memczak","year":"2013","journal-title":"Nature"},{"issue":"15","key":"pone.0329847.ref022","article-title":"Circular RNA CDR1as Exerts Oncogenic Properties Partially through Regulating MicroRNA 641 in Cholangiocarcinoma","volume":"40","author":"D Li","year":"2020","journal-title":"Molecular and Cellular Biology"},{"issue":"9","key":"pone.0329847.ref023","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.tips.2021.06.006","article-title":"In vivo functions of p75NTR: challenges and opportunities for an emerging therapeutic target","volume":"42","author":"SC Malik","year":"2021","journal-title":"Trends in Pharmacological Sciences"},{"issue":"12","key":"pone.0329847.ref024","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1038\/s43018-021-00272-y","article-title":"Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism","volume":"2","author":"S Garc\u00eda-Silva","year":"2021","journal-title":"Nat Cancer"},{"issue":"8","key":"pone.0329847.ref025","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.ejso.2008.10.013","article-title":"Patterns of expression and function of the p75NGFR protein in pancreatic cancer cells and tumours","volume":"35","author":"W Wang","year":"2009","journal-title":"Eur J Surg Oncol"},{"key":"pone.0329847.ref026","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2020.619730","article-title":"AMPK\/mTOR Signaling in Autophagy Regulation During Cisplatin-Induced Acute Kidney Injury","volume":"11","author":"Y Wang","year":"2020","journal-title":"Front Physiol"},{"key":"pone.0329847.ref027","doi-asserted-by":"crossref","first-page":"102344","DOI":"10.1016\/j.redox.2022.102344","article-title":"TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS\/AMPK\/mTOR\/autophagy signaling","volume":"53","author":"W Liu","year":"2022","journal-title":"Redox Biology"},{"issue":"1","key":"pone.0329847.ref028","article-title":"Copper-Based Nanomaterials for Image-Guided Cancer Therapy","volume":"5","author":"H Xu","year":"2024","journal-title":"BIOI"},{"issue":"3","key":"pone.0329847.ref029","article-title":"Targeted Imaging of Tumor Associated Macrophages in Breast Cancer","volume":"4","author":"Y Xu","year":"2022","journal-title":"BIOI"},{"issue":"1","key":"pone.0329847.ref030","article-title":"Non-Invasive Physical Stimulation to Modulate the Tumor Microenvironment: Unveiling a New Frontier in Cancer Therapy","volume":"5","author":"Z Guo","year":"2024","journal-title":"BIOI"},{"issue":"1","key":"pone.0329847.ref031","doi-asserted-by":"crossref","DOI":"10.15212\/bioi-2024-0066","article-title":"Integrated Network Ethnopharmacology, Molecular Docking, and ADMET Analysis Strategy for Exploring the Anti-Breast Cancer Activity of Ayurvedic Botanicals Targeting the Progesterone Receptor","volume":"5","author":"A Mokashi","year":"2024","journal-title":"BIOI"},{"key":"pone.0329847.ref032","doi-asserted-by":"crossref","first-page":"0080","DOI":"10.34133\/research.0080","article-title":"Intermittent F-actin Perturbations by Magnetic Fields Inhibit Breast Cancer Metastasis","volume":"6","author":"X Ji","year":"2023","journal-title":"Research"},{"issue":"2","key":"pone.0329847.ref033","doi-asserted-by":"crossref","first-page":"10","DOI":"10.53388\/TMR20220207263","article-title":"A comprehensive review of research progress in Chinese medicines for primary liver cancer treatment","volume":"7","author":"K Liao","year":"2022","journal-title":"Tradit Med Res"},{"issue":"1","key":"pone.0329847.ref034","doi-asserted-by":"crossref","first-page":"1","DOI":"10.53388\/TMR20211227255","article-title":"The artificial intelligence watcher predicts cancer risk by facial features","volume":"7","author":"H Zhang","year":"2022","journal-title":"Tradit Med Res"},{"issue":"9","key":"pone.0329847.ref035","doi-asserted-by":"crossref","first-page":"114697","DOI":"10.1016\/j.celrep.2024.114697","article-title":"Voluntary exercise sensitizes cancer immunotherapy via the collagen inhibition-orchestrated inflammatory tumor immune microenvironment","volume":"43","author":"Z Luo","year":"2024","journal-title":"Cell Reports"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0329847","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T17:35:20Z","timestamp":1754328920000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0329847"}},"subtitle":[],"editor":[{"given":"Zhiwen","family":"Luo","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,8,4]]},"references-count":35,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0329847","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2025,8,4]]}}}