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.

Analysis of Let-7 Family miRNA in Plasma as Potential Predictive Biomarkers of Diagnosis for Papillary Thyroid Cancer

“…This represents an opportunity to avoid severe side-effects of cancer treatments by using lower chemotherapy dosages. Acute myeloid leukemia, lung cancers, and chemoresistant epithelial ovarian cancers are characterized by a reduced let-7 resulting in nonresponse to chemotherapy [38][39][40][41][42][43]. Interestingly, decreased expression of let-7 was associated with significantly shorter survival after resection and may have a prognostic impact on the survival of surgically-treated lung cancer patients [44].…”

Roles of microRNAs and RNA-Binding Proteins in the Regulation of Colorectal Cancer Stem Cells

“…Downregulation of let-7 enhances the expression of its target genes, such as RAS, MYC and HMGA2, and promotes cancer initiation and progression [ 155 , 156 , 157 ]. Low expression of let-7 and high expression of LIN28 in non-small cell lung cancer patients was associated significantly with resistance to radiotherapy or chemotherapy [ 158 ]. LIN28 also exerts biological effects that are independent of let-7 miRNAs through selective binding to a large number of mRNAs.…”

Curcumin Inhibits LIN-28A through the Activation of miRNA-98 in the Lung Cancer Cell Line A549

“…MiR-98 overexpression was shown to suppress tumor cell proliferation [ 11 , 12 ], epithelial-mesenchymal transition (EMT), chemoresistance [ 13 ], and metastasis [ 14 ] by targeting p21 (RAC1)-activated kinase 1, SNAIL, and LIN28 [ 15 , 16 , 17 ], while its inhibition leads to tumor metastasis and poor clinical outcome [ 14 , 16 ]. Downregulation of let-7/miR-98 family members in various types of cancer results in increased expression of LIN28 [ 18 ], which is an important regulator of developmental timing [ 19 ] and is associated with tumorigenesis, metastasis, and poor clinical outcome [ 20 ]. The mammalian homologs of LIN28, LIN28A and LIN28B, bind to the terminal loops of the precursors of let-7/miR-98 family miRNAs [ 21 ].…”