{"doi":"10.1002/ctm2.1357","title":"A peek at the other side of the coin: Tumor‐suppressor role of microRNAs expressed by pancreatic cancer‐associated fibroblasts","abstract":"To the Editor: One of the most distinguishable characteristics of pancreatic ductal adenocarcinoma (PDAC) is its extensive desmoplastic stroma, and alpha smooth muscle actin (αSMA)-expressing cancer-associated fibroblasts (CAFs) that represent the largest component of this tumor-associated stroma (TAS). It is well established that reciprocal cancer-stroma cell interactions within the PDAC microenvironment influence cancer progression, response to chemotherapy, and immune tolerance. microRNAs (miRNAs) are small non-coding RNAs that contribute to the regulation of gene expression. Their biological impact on cancers can be both oncogenic (onco-miR) or tumor suppressive (TS-miR).1 miRNAs transported by extracellular vesicles (EVs) are effective communicators in tumor microenvironment (TME), and miRNA-RNA networks influence core PDAC signaling pathways during tumorigenesis. By and large, CAF-derived miRNAs are perceived as oncogenic (onco-miR), contributing to chemoresistance, metastasis, and progression. In contrast, our group reported that CAF-derived miR-145-5p, efficiently transferred to adjacent PDAC cells, inhibits growth and induces apoptosis in cultured PDAC cells.2 Others have recently reported similar findings; CAFs dynamically express tumor-suppressive miRNA in various cancers.3 This inspired us to reinvestigate the role of CAF-derived miRNAs in greater depth. We previously identified a set of miRNAs specifically and abundantly expressed in PDAC-derived primary CAFs using nanoCount miRNA profiling (nanoString).4 Here, we focused on an in silico analysis on a set of miRNAs differentially expressed by pancreatic CAFs (deCAF-miRNAs) and explored the other side of the coin—their putative tumor-suppressive proprieties. Starting with the most abundantly expressed deCAF-miRNA, we first performed a thorough, systematic literature search on the Medline database using the PubMed search engine and excluded those that have less than 20 reported studies. Ingenuity pathway analysis (IPA) further defined a final set of six deCAF-miRNAs specifically involved in pancreatic adenocarcinoma signaling (see Document S1 for methods). These are miR-145-5p and miR-199a-5p, followed by miR-136-5p, miR-137-3p, miR-127-3p, and miR-139-3p (in order of expression abundance, Table S1). To our surprise, an overwhelming number of research articles (95.2%, 550/578) described this set of deCAF-miRNAs as tumor-suppressive, whereas only 4.8% (28/578) of studies supported a variety of oncogenic properties across cancer types (Figure 1A and Table S1). This included the reported function of downregulating tumor progression (inhibited cellular proliferation, activated apoptosis, and increased chemosensitivity, etc.) in the in vitro studies, and reduced tumor growth and/or increased survival in the in vivo studies. Noticeably, the top two most abundant deCAF-miRNAs, that is, miR-145-5p and miR-199a-5p, were primarily tumor suppressive, documented in 97.7% (339/347) and 89.5% (111/124) articles, respectively. These data indicate a strong potency of the antitumor property of the set of deCAF-miRNAs. Alas, scarce data are obtainable regarding these miRNAs or their impact on PDAC specifically. Yet miR-145-5p (11 studies), miR-137-3p (five studies), and miR-139-3p (one study) have in consonance shown their antitumor function in PDAC (Table S1). Given the finite number of reports, the data clearly warrant further investigation to better understand the actual role of CAF-derived miRNAs. miRNA regulation forges miRNA-RNA networks that heavily converge on tumorigenesis signaling pathways. Thus, we next asked to what extent this set of defined deCAF-miRNAs influences the PDAC core pathways. miRNA target filter identified a total of 11 mRNA targets from the six deCAF-miRNAs (within experimental evidence or high confidence prediction) functionally relevant to pancreatic adenocarcinoma signaling pathways (Figure 1B and Table S2). Interestingly, the top two deCAF-miRNAs appea","journal":"Clinical and Translational Medicine","year":2023,"id":386555,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1008517,"name":"Aaron Davidson","orcid":null,"position":1,"is_corresponding":false},{"id":400008,"name":"Kelly M. Herremans","orcid":"0000-0002-0454-0931","position":2,"is_corresponding":false},{"id":367757,"name":"Chris E. Forsmark","orcid":null,"position":3,"is_corresponding":false},{"id":273483,"name":"Weizhou Zhang","orcid":"0000-0002-8236-0346","position":4,"is_corresponding":false},{"id":374591,"name":"Steven J. Hughes","orcid":"0000-0002-5688-6942","position":5,"is_corresponding":false},{"id":374590,"name":"Song Han","orcid":"0000-0002-6542-335X","position":6,"is_corresponding":false},{"id":901644,"name":"Gerik W. Tushoski-Alemán","orcid":"0000-0002-8191-4044","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T01:18:00.717763Z","pmid":"37539872","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":[]}