MUC1-C Induces the LIN28B→LET-7→HMGA2 Axis to Regulate Self-Renewal in NSCLC

Alam, Maroof; Ahmad, Rehan; Rajabi, Hasan; Küfe, Donald

doi:10.1158/1541-7786.mcr-14-0363

Cited by 54 publications

(51 citation statements)

References 52 publications

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“…LIN28B and HMGA2 are the two major targets related to EMT, as confirmed by three microRNA databases: TargetScanHuman 7.0 (www.targetscan.org), miRDB (www.mirdb.org), and www.microRNA.org. Let-7, LIN28B, and HMGA2 have been reported to form an axis to adjust the EMT process [13, 14, 32]. In our current study, we also noticed the significant upregulation of LIN28B and HMGA2 after transfection of let-7i mimic followed by co-culturing with A375 or SK-MEL-28 cell-derived exosomes vs controls.…”

Section: Discussionsupporting

confidence: 76%

Melanoma cell–derived exosomes promote epithelial–mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

et al. 2016

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The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma.

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Section: Discussionsupporting

confidence: 76%

Melanoma cell–derived exosomes promote epithelial–mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

et al. 2016

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“…As a direct target of the let-7 family, HMGA2 could function as the effector in the Lin28B-Let-7 axis (35). In a mouse model of breast cancer, HMGA2 has been shown to activate TGFbR2, and their colocalization has been observed in the invasive front of tumors (35,36).…”

Section: Resultsmentioning

confidence: 99%

HMGA2–FOXL2 Axis Regulates Metastases and Epithelial-to-Mesenchymal Transition of Chemoresistant Gastric Cancer

Dong

Wang

Ren

et al. 2017

Clinical Cancer Research

128

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Purpose: Chemoresistance is the main cause of treatment failure in cancer and is associated with distant metastases and epithelial-tomesenchymal transition (EMT). This study was aimed to explore the mechanism of metastases and EMT in chemoresistant gastric cancer.Experimental Design: A key molecular pathway was identified via gene profiling and a bioinformatic analysis in a chemoresistant gastric cancer model. The roles of FOXL2, HMGA2, and ITGA2 were validated via loss-of-function and gain-of-function experiments in vitro and in an orthotopic gastric cancer animal model. The regulation of FOXL2 by HMGA2 was explored via immunoprecipitation and luciferase reporter assays. The expression of these proteins in gastric cancer tissues was examined by IHC.Results: HMGA2 and FOXL2 directly regulated the metastasis and EMT of chemoresistant gastric cancer. The interaction between HMGA2 and pRb facilitated the transactivation of FOXL2 by E2F1, and ITGA2 was the downstream effector of the HMGA2-FOXL2 pathway. HMGA2, FOXL2, and ITGA2 were associated with the TNM classification and staging of gastric cancer and were increased in metastatic lymph nodes and distant metastases. Increased HMGA2, FOXL2, and ITGA2 levels were associated with reduced overall survival periods of patients with gastric cancer.Conclusions: This study demonstrated that the transactivation of FOXL2 driven by interactions between HMGA2 and pRb might exert critical effects on the metastases and EMT of chemoresistant gastric cancer. Blocking the HMGA2-FOXL2-ITGA2 pathway could serve as a new strategy for gastric cancer treatment.

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“…However, MYCN mRNA is suppressed by the let-7 miRNA 65 and, intriguingly, MUC1-C has been linked to the activation of LIN28B and downregulation of let-7. 66 Thus, how MUC1-C activates MYCL and MYCN will require further study. With regard to MYCdriven genes, we confirmed selected results from the array data by demonstrating that targeting MUC1-C decreases cyclin D2 mRNA and protein levels.…”

Section: Muc1-c Correlates With Myc Expression In Primary MM Cellsmentioning

confidence: 99%

MUC1-C drives MYC in multiple myeloma

Tagde

Rajabi

Bouillez

et al. 2016

Blood

Self Cite

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• MUC1-C induces MYC gene transcription in MM cells.• Targeting MUC1-C downregulates MYC expression and its transcriptional program.Multiple myeloma (MM) cell lines and primary tumor cells are addicted to the MYC oncoprotein for survival. Little is known, however, about how MYC expression is upregulated in MM cells. The mucin 1 C-terminal subunit (MUC1-C) is an oncogenic transmembrane protein that is aberrantly expressed in MM cell lines and primary tumor samples. The present studies demonstrate that targeting MUC1-C with silencing by clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 editing or with the GO-203 inhibitor is associated with downregulation of MYC messenger RNA and protein.The results show that MUC1-C occupies the MYC promoter and thereby activates the MYC gene by a b-catenin/transcription factor 4 (TCF4)-mediated mechanism. In this way, MUC1-C (1) increases b-catenin occupancy on the MYC promoter, (2) forms a complex with b-catenin and TCF4, and, in turn, (3) drives MYC transcription. Analysis of MM cells using quantitative real-time reverse transcription polymerase chain reaction arrays further demonstrated that silencing MUC1-C is associated with downregulation of MYC target genes, including CCND2, hTERT, and GCLC. Analysis of microarray data sets further demonstrated that MUC1 levels positively correlate with MYC expression in MM progression and in primary cells from over 800 MM patients. These findings collectively provide convincing evidence that MUC1-C drives

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MUC1-C Induces the LIN28B→LET-7→HMGA2 Axis to Regulate Self-Renewal in NSCLC

Cited by 54 publications

References 52 publications

Melanoma cell–derived exosomes promote epithelial–mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

Melanoma cell–derived exosomes promote epithelial–mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

HMGA2–FOXL2 Axis Regulates Metastases and Epithelial-to-Mesenchymal Transition of Chemoresistant Gastric Cancer

MUC1-C drives MYC in multiple myeloma

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