Lin28 regulates HER2 and promotes malignancy through multiple mechanisms

Chen, Feng; Neumeister, Veronique; Ma, Wei; Xu, Jie; Lu, Lingeng; Bordeaux, Jennifer; Maihle, Nita J.; Rimm, David L.; Huang, Yingqun

doi:10.4161/cc.20893

Cited by 63 publications

(60 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The expressions of both LIN28 and ENAH have been independently shown to promote malignancy of HER2 breast cancers, but the molecular mechanisms underlying these effects have not been linked (28,46,61). Our study provides evidence suggesting that LIN28 modulates the splicing and expression of human ENAH isoforms that are critical for HER2 signaling in breast cancer cells.…”

Section: Discussionmentioning

confidence: 54%

See 1 more Smart Citation

LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells

Yang

Bennett

Luo

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

LIN28 is an evolutionarily conserved RNA-binding protein with critical functions in developmental timing and cancer. However, the molecular mechanisms underlying LIN28's oncogenic properties are yet to be described. RNA-protein immunoprecipitation coupled with genome-wide sequencing (RIP-Seq) analysis revealed significant LIN28 binding within 843 mRNAs in breast cancer cells. Many of the LIN28-bound mRNAs are implicated in the regulation of RNA and cell metabolism. We identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), a protein with multiple roles in mRNA metabolism, as a LIN28-interacting partner. Subsequently, we used a custom computational method to identify differentially spliced gene isoforms in LIN28 and hnRNP A1 small interfering RNA (siRNA)-treated cells. The results reveal that these proteins regulate alternative splicing and steady-state mRNA expression of genes implicated in aspects of breast cancer biology. Notably, cells lacking LIN28 undergo significant isoform switching of the ENAH gene, resulting in a decrease in the expression of the ENAH exon 11a isoform. The expression of ENAH isoform 11a has been shown to be elevated in breast cancers that express HER2. Intriguingly, analysis of publicly available array data from the Cancer Genome Atlas (TCGA) reveals that LIN28 expression in the HER2 subtype is significantly different from that in other breast cancer subtypes. Collectively, our data suggest that LIN28 may regulate splicing and gene expression programs that drive breast cancer subtype phenotypes.

show abstract

Section: Discussionmentioning

confidence: 54%

“…LIN28 is expressed in breast cancer tumors, and recent studies have shown that LIN28 is a powerful predictor of poor prognoses and patient clinical outcomes (8,28,29). With this in mind, we were interested in identifying novel LIN28 mRNA targets that could provide insights into the function of LIN28 in breast cancer.…”

mentioning

confidence: 99%

LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells

Yang

Bennett

Luo

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…It is now evident that Lin28a is an important oncogene in tumorigenesis (Tu et al 2015) and an emerging maker of cancer stem cells (Ma et al 2014). For example, prolonged expression of Lin28a in primitive mesenchymal kidney cells resulted in increased cell proliferation and Wilms' tumor formation (Feng et al 2012), which strongly suggests that Lin28a-mediated regulation of miRNA production can transcend the niche of undifferentiated cells and affect other miRNAs that are important for proper developmental timing. Thus, studying the systems where Lin28a is overexpressed is of utmost importance to understand its various roles in cancer biology.…”

Section: Discussionmentioning

confidence: 99%

Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively

Nowak

Hóbor

Velasco

et al. 2016

RNA

View full text Add to dashboard Cite

Lin28a inhibits the biogenesis of let-7 miRNAs by triggering the polyuridylation and degradation of their precursors by terminal uridylyltransferases TUT4/7 and 3 ′ -5 ′ exoribonuclease Dis3l2, respectively. Previously, we showed that Lin28a also controls the production of neuro-specific miRNA-9 via a polyuridylation-independent mechanism. Here we reveal that the sequences and structural characteristics of pre-let-7 and pre-miRNA-9 are eliciting two distinct modes of binding to Lin28a. We present evidence that Dis3l2 controls miRNA-9 production. Finally, we show that the constitutive expression of untagged Lin28a during neuronal differentiation in vitro positively and negatively affects numerous other miRNAs. Our findings shed light on the role of Lin28a in differentiating cells and on the ways in which one RNA-binding protein can perform multiple roles in the regulation of RNA processing.

show abstract

“…3 In particular, overexpression of ErbB2 has been demonstrated to promote breast cancer invasion and metastasis and to correlate with poor patient survival. [4][5][6][7] However, ErbB2 is also overexpressed in non-invasive mammary ductal carcinomas in situ (DCIS). 8 Indeed, ErbB2 amplification or overexpression seems to be crucial but not sufficient for the transition from in situ to invasive cancer, and additional hits are required for the progression of ErbB2-positive tumors.…”

Section: Introductionmentioning

confidence: 99%

Identification of p130Cas/ErbB2-dependent invasive signatures in transformed mammary epithelial cells

et al. 2013

View full text Add to dashboard Cite

Understanding transcriptional changes during cancer progression is of crucial importance to develop new and more efficacious diagnostic and therapeutic approaches. It is well known that erbB2 is overexpressed in about 25% of human invasive breast cancers. We have previously demonstrated that p130Cas overexpression synergizes with erbB2 in mammary cell transformation and promotes erbB2-dependent invasion in 3-dimensional (3D) cultures of human mammary epithelial cells. Here, by comparing coding and non-coding gene expression profiles, we define the invasive signatures associated with concomitant p130Cas overexpression and erbB2 activation in 3D cultures of mammary epithelial cells. Specifically, we have found that genes involved in amino acids synthesis (CBS, PHGDH), cell motility, migration (ItPKa, PrDM1), and angiogenesis (Hey1) are upregulated, while genes involved in inflammatory response (Saa1, S100a7) are downregulated. In parallel, we have shown that the expression of specific mirNas is altered. among these, mir-200b, mir-222, mir-221, mir-r210, and mir-424 are upregulated, while mir-27a, mir-27b, and mir-23b are downregulated. overall, this study presents, for the first time, the gene expression changes underlying the invasive behavior following p130Cas overexpression in an erbB2 transformed mammary cell model.

show abstract

Lin28 regulates HER2 and promotes malignancy through multiple mechanisms

Cited by 63 publications

References 43 publications

LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells

LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells

Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively

Identification of p130Cas/ErbB2-dependent invasive signatures in transformed mammary epithelial cells

Contact Info

Product

Resources

About