Differential Regulation of LET-7 by LIN28B Isoform-Specific Functions

作者：Mizuno Rei; Chatterji Priya; Andres Sarah; Hamilton Kathryn; Simon Lauren; Foley Shawn W; Jeganathan Arjun; Gregory Brian D; Madison Blair; Rustgi Anil K^*

来源：Molecular Cancer Research, 2018, 16(3): 403-416.

DOI：10.1158/1541-7786.MCR-17-0514

The RNA-binding protein LIN28B plays an important role in development, stem cell biology, and tumorigenesis. LIN28B has two isoforms: the LIN28B-long and -short isoforms. Although studies have revealed the functions of the LIN28B-long isoform in tumorigenesis, the role of the LIN28B-short isoform remains unclear and represents a major gap in the field. The LIN28B-long and -short isoforms are expressed in a subset of human colorectal cancers and adjacent normal colonic mucosa, respectively. To elucidate the functional and mechanistic aspects of these isoforms, colorectal cancer cells (Caco-2 and LoVo) were generated to either express no LIN28B or the -short or -long isoform. Interestingly, the long isoform suppressed LET-7 expression and activated canonical RAS/ERK signaling, whereas the short isoform did not. The LIN28B-long isoform-expressing cells demonstrated increased drug resistance to 5-fluorouracil and cisplatin through the upregulation of ERCC1, a DNA repair gene, in a LET-7-dependent manner. The LIN28B-short isoform preserved its ability to bind pre-let-7, without inhibiting thematuration of LET-7, and competed with the LIN28B-long isoform for binding to pre-let-7. Coexpression of the short isoform in the LIN28B-long isoform-expressing cells rescued the phenotypes induced by the LIN28B-long isoform.

• 出版日期2018-3