Wnt/β-catenin pathway represses let-7 microRNAs expression via transactivation of Lin28 to augment breast cancer stem cell expansion

Cai, Wangyu; Wei, Tongzhen; Luo, Qin; Wu, Qiu-Wan; Li, Qingfeng; Meng, Yan; Ye, Guodong; Wu, Jiafa; Chen, Yuanyuan; Sun, Guangbin; Liu, Yunjia; Zhao, Wenxiu; Zhang, Zhiming; Li, Boan

doi:10.1242/jcs.123810

Cited by 126 publications

(101 citation statements)

References 56 publications

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“…As a previous report concluded that activated Wnt signaling up-regulates Lin28a in breast cancer cells (Cai et al 2013), we determined the levels of Lin28a in the Apc Min/+ tumors and failed to detect expression (Supplemental Fig. 4A).…”

Section: Lin28 Promotes Proliferation and Inhibits Differentiation Ofmentioning

confidence: 97%

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

Schwitalla

Qian

et al. 2015

Genes Dev.

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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.

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Section: Lin28 Promotes Proliferation and Inhibits Differentiation Ofmentioning

confidence: 97%

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

Schwitalla

Qian

et al. 2015

Genes Dev.

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“…It is possible that the conserved tumor suppressor function of the let-7 microRNA (57, 58) may in part reflect conserved roles in regulating LIT-1/POP-1/APR-1 asymmetry and hence promoting asymmetric (nonproliferative) cell division. Similarly, the conserved role for LIN-28 in promoting stem cell fate in diverse contexts, including cancer (17,59,60), may reflect a general activity for LIN-28 in opposing LIT-1/POP-1/APR-1 stem cell division asymmetry.…”

Section: Stage-specific Heterochronic Gene Activities Promoting Seam mentioning

confidence: 99%

Control of stem cell self-renewal and differentiation by the heterochronic genes and the cellular asymmetry machinery in Caenorhabditis elegans

Harandi

Ambros

2015

Proc. Natl. Acad. Sci. U.S.A.

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Transitions between asymmetric (self-renewing) and symmetric (proliferative) cell divisions are robustly regulated in the context of normal development and tissue homeostasis. To genetically assess the regulation of these transitions, we used the postembryonic epithelial stem (seam) cell lineages of Caenorhabditis elegans. In these lineages, the timing of these transitions is regulated by the evolutionarily conserved heterochronic pathway, whereas cell division asymmetry is conferred by a pathway consisting of Wnt (Wingless) pathway components, including posterior pharynx defect (POP-1)/TCF, APC related/adenomatosis polyposis coli (APR-1)/APC, and LIT-1/NLK (loss of intestine/Nemo-like kinase). Here we explore the genetic regulatory mechanisms underlying stage-specific transitions between self-renewing and proliferative behavior in the seam cell lineages. We show that mutations of genes in the heterochronic developmental timing pathway, including lin-14 (lineage defect), lin-28, lin-46, and the lin-4 and let-7 (lethal defects)-family microRNAs, affect the activity of LIT-1/POP-1 cellular asymmetry machinery and APR-1 polarity during larval development. Surprisingly, heterochronic mutations that enhance LIT-1 activity in seam cells can simultaneously also enhance the opposing, POP-1 activity, suggesting a role in modulating the potency of the cellular polarizing activity of the LIT-1/ POP-1 system as development proceeds. These findings illuminate how the evolutionarily conserved cellular asymmetry machinery can be coupled to microRNA-regulated developmental pathways for robust regulation of stem cell maintenance and proliferation during the course of development. Such genetic interactions between developmental timing regulators and cell polarity regulators could underlie transitions between asymmetric and symmetric stem cell fates in other systems and could be deregulated in the context of developmental disorders and cancer.uring development and tissue regeneration, stem cells generate cellular diversity through asymmetric divisions that produce a stem cell and a differentiated cell, or alternatively, through symmetric divisions that produce either two stem cells or two differentiated cells (Fig. 1A). The proper regulation of asymmetric vs. symmetric cell division patterns for stem cells is fundamental to the elaboration of developmental patterns of cell fate and for tissue growth and homeostasis (1, 2). Many of the genes that are involved in the regulation of stem cell division asymmetry are evolutionarily conserved and have been found to be associated with carcinogenesis, underlining the biomedical significance of understanding this process (3-5).In Caenorhabditis elegans, the lateral hypodermal cell lineages display developmentally regulated transitions between asymmetric and symmetric divisions, providing a model to study the control of stem cell division behavior in vivo (6-8). These stem cells (called "seam" cells) are aligned along each side of the animal (Fig. 1B). Seam cells undergo a single round of as...

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“…This finding suggests that LIN28B a novel direct downstream target gene of the Wnt/b-catenin pathway. Interestingly, a recent research revealed that LEF1, another effector of Wnt/b-catenin pathway, could activate LIN28A via direct binding to the LIN28A promoter (27). This report provided compelling evidence that both LIN28A and LIN28B were direct target genes of the Wnt/b-catenin pathway.…”

Section: Discussionmentioning

confidence: 63%

“…In fact, it has been reported that LIN28A/LIN28B can promote transformation by repressing let-7 miRNAs, and that activation of LIN28A/LIN28B occurs in many different human tumors with a frequency of approximately 15% (23,24). Recent studies have also suggested that LIN28 plays an important role in the maintenance of CSCs (25,26) and Wnt signaling could directly activate LIN28 to augment breast cancer stem cell expansion (27).…”

Section: Introductionmentioning

confidence: 99%

IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis

et al. 2015

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Considerable evidence suggests that proinflammatory pathways drive self-renewal of cancer stem-like cells (CSC), but the underlying mechanisms remain mainly undefined. Here we report that the let7 repressor LIN28B and its regulator IKBKB (IKKb) sustain cancer cell stemness by interacting with the Wnt/TCF7L2 (TCF4) signaling pathway to promote cancer progression. We found that LIN28B expression correlated with clinical progression and stemness marker expression in breast cancer patients. Functional studies demonstrated that the stemness properties of LIN28B-expressing human breast and lung cancer cells were enhanced by IKKb, whereas loss of LIN28B abolished stemness properties in these settings. These phenomena were driven through interactions with TCF7L2, which enhanced LIN28B expression by direct binding to intron 1 of the LIN28B gene, which in turn promoted TCF7L2 mRNA translation through a positive feedback loop. Notably, RNAimediated silencing of LIN28B or pharmacologic inhibition of IKKb was sufficient to suppress primary and metastatic tumor growth in vivo. Together, our results establish the LIN28B/ TCF7L2 interaction loop as a central mediator of cancer stemness driven by proinflammatory processes during progression and metastasis, possibly offering a new therapeutic target for generalized interventions in advanced cancers.

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Wnt/β-catenin pathway represses let-7 microRNAs expression via transactivation of Lin28 to augment breast cancer stem cell expansion

Cited by 126 publications

References 56 publications

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

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

Control of stem cell self-renewal and differentiation by the heterochronic genes and the cellular asymmetry machinery in Caenorhabditis elegans

IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis

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