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The LIN28/let-7 Pathway in Cancer
Julien Balzeau1, Miriam R Menezes1, Siyu Cao1
1Department of Neurosurgery, University of Texas Health Science Center at Houston Houston, TX, USA.
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.
Insights
Reduced let-7 microRNA expression, driven by LIN28A/LIN28B, is common in cancer, promoting tumor growth and poor prognosis. Targeting this LIN28/let-7 pathway shows therapeutic promise.
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Reduced let-7 microRNA expression is a frequent event in cancer, correlating with poor patient outcomes.
- LIN28A and LIN28B, proto-oncogenes, downregulate let-7 microRNAs post-transcriptionally in various cancers.
- LIN28A recruits ZCCHC11 (TUTase) to polyuridylate pre-let-7, inhibiting its biogenesis and tumor suppressor activity.
Purpose of the Study:
- To review the role of the LIN28/let-7 pathway in cancer.
- To discuss the pathway's involvement in tumorigenesis, cancer stem cell biology, metabolomics, metastasis, and treatment resistance.
- To highlight emerging therapeutic strategies targeting the LIN28/let-7 axis.
Main Methods:
- Literature review of studies investigating the LIN28/let-7 pathway.
- Analysis of molecular mechanisms underlying let-7 downregulation by LIN28A and LIN28B.
- Examination of preclinical and clinical evidence regarding the pathway's function in cancer.
Main Results:
- LIN28A/LIN28B activation leads to decreased let-7 levels, resulting in the overexpression of oncogenic targets like MYC and RAS.
- Ectopic LIN28 expression in mouse models accelerates tumorigenesis through a let-7 dependent mechanism.
- The LIN28/let-7 pathway influences cancer stem cell properties, metabolism, metastasis, and resistance to radiation and chemotherapy.
Conclusions:
- The LIN28/let-7 pathway is a critical regulator in cancer development and progression.
- Dysregulation of this pathway contributes to various hallmarks of cancer.
- Targeting the LIN28/let-7 axis represents a promising therapeutic avenue for cancer treatment.