SALL4 and microRNA: The Role of Let-7

Abstract

SALL4 is a zinc finger transcription factor that belongs to the spalt-like (SALL) gene family. It plays important roles in the maintenance of self-renewal and pluripotency of embryonic stem cells, and its expression is repressed in most adult organs. SALL4 re-expression has been observed in different types of human cancers, and dysregulation of SALL4 contributes to the pathogenesis, metastasis, and even drug resistance of multiple cancer types. Surprisingly, little is known regarding how SALL4 expression is controlled, but recently microRNAs (miRNAs) have emerged as important regulators of SALL4. Due to the ability of regulating targets differentially in specific tissues, and recent advances in systemic and organ specific miRNA delivery mechanisms, miRNAs have emerged as promising therapeutic targets for cancer treatment. In this review, we summarize current knowledge of the interaction between SALL4 and miRNAs in mammalian development and cancer, paying particular attention to the emerging roles of the Let-7/Lin28 axis. In addition, we discuss the therapeutic prospects of targeting SALL4 using miRNA-based strategies, with a focus on the Let-7/LIN28 axis.

Keywords: LIN28; Let-7; SALL4; hepatocellular carcinoma (HCC); miR-98; microRNA; non-small cell lung cancer (NSCLC).

Figure 1

Flow chart of article screening, inclusion, and exclusion.

Figure 2

Summary of Spalt-like (SALL4)-interacting microRNAs: Multiple microRNAs have been shown to regulate SALL4 in a variety of cancer types, including glioma, acute myeloid leukemia (AML), hepatocellular carcinoma (HCC), gastric cancer, ovarian cancer, lung cancer, colorectal cancer, and breast cancer. In addition, SALL4 acts as an upstream regulator of the expression of miR-200c and miR-146a in HCC.

Figure 3

Strategies in targeting miR/SALL4 axis in cancer. We can inhibit SALL4 protein expression through miRs by (1) using LIN28 inhibitors to block its repression on Let 7/miR-98 which in turn decreases SALL4 expression (2) use of epigenetic drugs such as HDAC inhibitor Entinostat to upregulate miR-205, which in turn suppresses SALL4 expression. Solid lines represent experimentally validated epistatic relationships.