LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans

Abstract

Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc Min/+ mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target.

Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively

“…Both Lin28a and Lin28b are misexpressed in a number of tumor and cancer cells Zhou et al 2013). It is now evident that Lin28a is an important oncogene in tumorigenesis (Tu et al 2015) and an emerging maker of cancer stem cells (Ma et al 2014). For example, prolonged expression of Lin28a in primitive mesenchymal kidney cells resulted in increased cell proliferation and Wilms' tumor formation (Feng et al 2012), which strongly suggests that Lin28a-mediated regulation of miRNA production can transcend the niche of undifferentiated cells and affect other miRNAs that are important for proper developmental timing.…”

The LIN28/let-7 Pathway in Cancer

“…Three independent groups have each analyzed more than 200 colon cancer samples where LIN28AB expression has been shown to be associated with poor prognosis (see Table 1). To investigate a direct role for Lin28ab in mammalian intestinal and colon cancer, the Daley lab used mice with doxycycline inducible Lin28A/LIN28B expression that was limited to cells where Villin-Cre had acted (Tu et al, 2015). They showed that induced Lin28A/LIN28B expression was sufficient to cause tumors restricted to the small intestine.…”

Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

“…Likewise, p53, a tumor suppressor protein frequently inactivated/silenced during the evolution from advanced adenoma to adenocarcinoma, is controlled by miR-34a/b/c, miR-133a, miR-143, and miR-145 174, 181–183 . In contrast, genes such as LIN28 drive CRC progression through inhibition of let-7 miRNA biogenesis, highlighting the complexity of miRNA-gene interaction in cancer 184, 185 . In addition, miR-21, miR-155 and miR-200 family members regulate the TGF-ß pathway 186–188 .…”