Abstract
Among all tumor suppressor microRNAs, reduced let-7 expression occurs most frequently in cancer and typically correlates with poor prognosis. Activation of either LIN28A or LIN28B, two highly related RNA binding proteins (RBPs) and proto-oncogenes, is responsible for the global post-transcriptional downregulation of the let-7 microRNA family observed in many cancers. Specifically, LIN28A binds the terminal loop of precursor let-7 and recruits the Terminal Uridylyl Transferase (TUTase) ZCCHC11 that polyuridylates pre-let-7, thereby blocking microRNA biogenesis and tumor suppressor function. For LIN28B, the precise mechanism responsible for let-7 inhibition remains controversial. Functionally, the decrease in let-7 microRNAs leads to overexpression of their oncogenic targets such as MYC, RAS, HMGA2, BLIMP1, among others. Furthermore, mouse models demonstrate that ectopic LIN28 expression is sufficient to drive and/or accelerate tumorigenesis via a let-7 dependent mechanism. In this review, the LIN28/let-7 pathway is discussed, emphasizing its role in tumorigenesis, cancer stem cell biology, metabolomics, metastasis, and resistance to ionizing radiation and several chemotherapies. Also, emerging evidence will be presented suggesting that molecular targeting of this pathway may provide therapeutic benefit in cancer.
Highlights
MicroRNAs (miRNAs) are small non-coding RNAs (∼19–22 nucleotides in length) that play critical roles in post-transcriptional gene regulation (reviewed in Hagan and Croce, 2007; Lin and Gregory, 2015b; Connerty et al, 2016)
MicroRNAs are small non-coding RNAs (∼19–22 nucleotides in length) that play critical roles in post-transcriptional gene regulation
Lin-28 and the microRNA let-7 were initially discovered in C. elegans as heterochronic genes that regulate developmental timing
Summary
MicroRNAs (miRNAs) are small non-coding RNAs (∼19–22 nucleotides in length) that play critical roles in post-transcriptional gene regulation (reviewed in Hagan and Croce, 2007; Lin and Gregory, 2015b; Connerty et al, 2016). We showed that inhibition of either LIN28A or LIN28B via siRNA led to regression of established human xenograft tumors in mice that expressed the targeted gene (Piskounova et al, 2011). A study conducted by Viswanathan and colleagues using primary human tumors and human cancer cell lines showed that about 15% of human cancers displayed high LIN28A/LIN28B and low let-7 expression pattern.
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