{"doi":"10.1093/carcin/bgac092","title":"Dysregulation of HNF1B/Clusterin axis enhances disease progression in a highly aggressive subset of pancreatic cancer patients","abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is largely refractory to available treatments. Identifying key pathways associated with disease aggressiveness and therapeutic resistance may characterize candidate targets to improve patient outcomes. We used a strategy of examining the tumors from a subset of PDAC patient cohorts with the worst survival to understand the underlying mechanisms of aggressive disease progression and to identify candidate molecular targets with potential therapeutic significance. Non-negative matrix factorization (NMF) clustering, using gene expression profile, revealed three patient subsets. A 142-gene signature specific to the subset with the worst patient survival, predicted prognosis and stratified patients with significantly different survival in the test and validation cohorts. Gene-network and pathway analysis of the 142-gene signature revealed dysregulation of Clusterin (CLU) in the most aggressive patient subset in our patient cohort. Hepatocyte nuclear factor 1 b (HNF1B) positively regulated CLU, and a lower expression of HNF1B and CLU was associated with poor patient survival. Mechanistic and functional analyses revealed that CLU inhibits proliferation, 3D spheroid growth, invasiveness and epithelial-to-mesenchymal transition (EMT) in pancreatic cancer cell lines. Mechanistically, CLU enhanced proteasomal degradation of EMT-regulator, ZEB1. In addition, orthotopic transplant of CLU-expressing pancreatic cancer cells reduced tumor growth in mice. Furthermore, CLU enhanced sensitivity of pancreatic cancer cells representing aggressive patient subset, to the chemotherapeutic drug gemcitabine. Taken together, HNF1B/CLU axis negatively regulates pancreatic cancer progression and may potentially be useful in designing novel strategies to attenuate disease progression in PDAC patients.","journal":"Carcinogenesis","year":2022,"id":238410,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":55,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":276003,"name":"Wei Tang","orcid":"0000-0002-7089-4391","position":1,"is_corresponding":false},{"id":862165,"name":"Azadeh Azizian","orcid":"0000-0003-4270-5706","position":2,"is_corresponding":false},{"id":862166,"name":"Jochen Gaedcke","orcid":"0000-0002-6130-5874","position":3,"is_corresponding":false},{"id":680053,"name":"Philipp Ströbel","orcid":"0000-0002-8528-8060","position":4,"is_corresponding":false},{"id":90602,"name":"Limin Wang","orcid":"0000-0002-8849-9621","position":5,"is_corresponding":false},{"id":862167,"name":"Helen Cawley","orcid":"0009-0004-0967-2011","position":6,"is_corresponding":false},{"id":857717,"name":"Yuuki Ohara","orcid":"0000-0002-9171-4724","position":7,"is_corresponding":false},{"id":858383,"name":"Paloma Valenzuela","orcid":null,"position":8,"is_corresponding":false},{"id":318422,"name":"Lin Zhang","orcid":"0000-0002-3767-0249","position":9,"is_corresponding":false},{"id":829088,"name":"Trisha Lal","orcid":null,"position":10,"is_corresponding":false},{"id":3207,"name":"Sanju Sinha","orcid":"0000-0002-2688-0603","position":11,"is_corresponding":false},{"id":862724,"name":"Eythan Rupin","orcid":null,"position":12,"is_corresponding":false},{"id":862168,"name":"Nader Hanna","orcid":"0000-0001-5755-5910","position":13,"is_corresponding":false},{"id":862725,"name":"B. Michael Ghadimi","orcid":null,"position":14,"is_corresponding":false},{"id":276011,"name":"S. Perwez Hussain","orcid":"0000-0002-2294-522X","position":15,"is_corresponding":false},{"id":862723,"name":"Shouhui Yang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T00:22:26.932537Z","pmid":"36426859","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}