title: Disturbance of the let-7/LIN28 double-negative feedback loop is associated with radio- and chemo-resistance in non-small cell lung cancer.
abstract: Radio- and chemo-resistance represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC) and the underlying molecular mechanisms are not known. In the present study, during induction of radio- or chemo-resistance in NSCLC cells, dynamic analyses revealed that decreased expression of let-7 induced by irradiation or cisplatin resulted in increased expression of its target gene LIN28, and increased expression of LIN28 then contributed to further decreased expression of let-7 by inhibiting its maturation and biogenesis. Moreover, we showed that down-regulation of let-7 and up-regulation of LIN28 expression promoted resistance to irradiation or cisplatin by regulating the single-cell proliferative capability of NSCLC cells. Consequently, in NSCLC cells, let-7 and LIN28 can form a double-negative feedback loop through mutual inhibition, and disturbance of the let-7/LIN28 double-negative feedback loop induced by irradiation or chemotherapeutic drugs can result in radio- and chemo-resistance. In addition, low expression of let-7 and high expression of LIN28 in NSCLC patients was associated significantly with resistance to radiotherapy or chemotherapy. Therefore, our study demonstrated that disturbance of the let-7/LIN28 double-negative feedback loop is involved in the regulation of radio- and chemo-resistance, and that let-7 and LIN28 could be employed as predictive biomarkers of response to radiotherapy or chemotherapy in NSCLC patients.
authors.affiliation: Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Guangping
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Ruihao
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Linjing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Guoqian
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Wenfan
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Dai
authors.affiliation: Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Wanzhen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Boyu
authors.initials: B
authors.lastname: Liao
authors.affiliation: Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Shuxu
authors.initials: S
authors.lastname: Zhang
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: C000715187:Lin28A protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human; D002945:Cisplatin