title: The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL.
abstract: miR-21 expression in cancer tissue has been reported to be associated with the clinical outcome and activity of gemcitabine in pancreatic cancer. However, resection is possible in only a minority of patients due to the advanced stages often present at the time of diagnosis, and safely obtaining sufficient quantities of pancreatic tumor tissue for molecular analysis is difficult at the unresectable stages. In this study, we investigated whether the serum level of miR-21 could be used as a predictor of chemosensitivity. We tested the levels of serum miR-21 in a cohort of 177 cases of advanced pancreatic cancer who received gemcitabine-based palliative chemotherapy. We found that a high level of miR-21 in the serum was significantly correlated with a shortened time-to-progression (TTP) and a lower overall survival (OS). The serum miR-21 level was an independent prognostic factor for both the TTP and the OS (HR 1.920; 95% CI, 1.274-2.903, p = 0.002 for TTP and HR 1.705; 95% CI, 1.147-2.535, p = 0.008 for OS). The results from a functional study showed that gemcitabine exposure down-regulated miR-21 expression and up-regulated FasL expression. The increased FasL expression following gemcitabine treatment induced cancer cell apoptosis, whereas the ectopic expression of miR-21 partially protected the cancer cells from gemcitabine-induced apoptosis. Additionally, we confirmed that FasL was a direct target of miR-21. Therefore, the serum level of miR-21 may serve as a predictor of chemosensitivity in advanced pancreatic cancer. Additionally, we identified a new mechanism of chemoresistance mediated by the effects of miR-21 on the FasL/Fas pathway.
authors.affiliation: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Liping
authors.initials: L
authors.lastname: Zhuang
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.forename: Jianmin
authors.initials: J
authors.lastname: Luo
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Luming
authors.initials: L
authors.lastname: Liu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Meng
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015331:Cohort Studies; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D053222:Fas Ligand Protein; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D003841:Deoxycytidine; D000093542:Gemcitabine