LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7

Area of Science:

• Molecular Biology
• Developmental Biology
• Oncology

Background:

• LIN28A and LIN28B are RNA-binding proteins involved in stem cells, reprogramming, growth, and cancer.
• Their functions are often mediated by inhibiting Let-7 microRNAs (miRNAs).

Purpose of the Study:

• To investigate the role of LIN28B in intestinal tissue growth and cancer formation.
• To explore potential Let-7-independent functions of LIN28B.
• To elucidate the interplay between LIN28B, Let-7 miRNAs, and intestinal homeostasis.

Main Methods:

• Intestine-specific LIN28B expression in a mouse model.
• Ribonucleoprotein cross-linking, immunoprecipitation, and high-throughput sequencing (CLIP-seq) to identify LIN28B RNA targets.
• Genetic manipulation of Let-7 miRNA levels (mirLet7c2/mirLet7b gene deletion and intestine-specific Let-7 expression).

Main Results:

• LIN28B overexpression caused intestinal hypertrophy, crypt expansion, Paneth cell loss, and promoted polyp and adenocarcinoma formation.
• CLIP-seq identified numerous mRNA targets of LIN28B, with modest protein level augmentation.
• Modulation of Let-7 levels mimicked or reversed LIN28B-induced effects, indicating a dominant Let-7-dependent mechanism.
• Intestine-specific Let-7 expression reversed LIN28B-driven hypertrophy and Paneth cell depletion, independent of insulin-PI3K-mTOR signaling.

Conclusions:

• Let-7 miRNAs are crucial repressors of intestinal tissue growth and are essential for Paneth cell differentiation.
• LIN28B acts as an oncogene in the intestine, primarily through Let-7-dependent mechanisms.
• Let-7-dependent functions of LIN28B may be more significant than any Let-7-independent roles in intestinal tissue regulation and oncogenesis.