LIN28 (LIN28A) is a reprogramming factor and conserved RNA-binding protein. LIN28B is the only homolog of LIN28 in humans, sharing structure and certain function. LIN28/LIN28B has been identified to be overexpressed in a wide range of solid tumors and hematological malignancies. Blockage of let-7 miRNA biogensis and subsequent derepression of let-7 miRNA target genes by LIN28/LIN28B play important roles in cancer progression and metastasis. We will first provide an overview of LIN28/LIN28B gene and protein structures, followed by summary of the studies that showed their aberrant expression in primary human cancers and relevant clinical significance with emphasis on their roles in formation of cancer stem cells. Next, we will highlight the current knowledge of LIN28/LIN28B regulators and molecular mechanisms of LIN28/LIN28B-mediated oncogenesis. The potential medical applications for targeting LIN28/LIN28B will also be discussed in this review.
Models for conserved functions of RNA binding protein LIN28/LIN28B and different miRNAs in stem cells and cancer stem cells.
(A) A double-negative feedback loops between LIN28/LIN28B and let-7 regulates stem cell differentiation. High expression of LIN28/LIN28B and low let-7 are often observed in cancers, implying that stem cells and cancer cells share a common regulatory circuit balancing between self renewal and differentiation.
(B) Diagram of different mechanisms by which specifically upregulates or downregulates LIN28/LIN28B gene expression. ↓ signs indicate activation and ⊥ signs represent inhibition
Jianbiao Zhou1, Siok-Bian Ng1,2 and Wee-Joo Chng1,3,4
1Cancer Science Institute of Singapore, National University of Singapore,
2Department of Pathology, 3Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore,
4Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), Singapore