Abstract 120: Epidermal Growth Factor Receptor (EGFR) Family Dimeric Partners Switch During Pathological Stress in microRNA-7 Transgenic Mice

miRNA-7 is known to target epidermal growth factors receptor 1(EGFR1) in cancer cells. EGFR family members (EGFR 1, 2, 3 and 4) are known to form homo- and/or hetero-dimers to mediate downstream signals . Our previous study in human heart failure (Naga Prasad etal., JBC, 2009) showed that EGFR2 (ERBB2) was targeted by miRNA-7. Based on this study, we developed transgenic (Tg) mice with cardiomyocyte-specific overexpression of miRNA-7. miRNA-7 Tg mice have age dependent deterioration in cardiac dysfunction and is associated with cardiac dilation as measured by echocardiography (3 months - 60% FS, 6 month -52% FS &12 months - 24%FS) and yet, they survive well for more than a year. To investigate whether pathological stress would accelerate the deterioration in cardiac function, miRNA-7 Tg mice were subjected to transverse aortic constriction (TAC) for two weeks. In contrast to the wild type littermates which undergo hypertrophic response following TAC, miRNA-7 Tg mice have accelerated cardiac dysfunction and dilation within two weeks. Biochemical analysis interestingly showed differential switching of dimeric EGFR partners in hearts of the miRNA-7 Tg mice compared to their sham controls. Our presentation will discuss the differential downstream signaling induced by changing of EGFR dimeric partners induced by pathological stress like TAC in the wildtype and miRNA-7 Tg mice.

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Abstract 272: miRNA-7 Leads to Enhanced Fibrosis in the Heart

Circulation Research ◽

10.1161/res.119.suppl_1.272 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Manveen Gupta ◽

Xi Wang ◽

Elizabeth Martelli ◽

Prasad Sathyamangla

Keyword(s):

Cardiac Dysfunction ◽

Critical Role ◽

Human Heart Failure ◽

Hypertrophic Response ◽

Erbb2 Expression ◽

Kaplan Meier ◽

Response To Stress ◽

Epidermal Growth ◽

Egfr Family ◽

And Function

MicroRNA-7 (miR-7) is known to target epidermal growth factor receptors (EGFRs) in oncogenic cells however, less is known about its role and function in the heart. Our studies have identified reciprocal expression pattern for ERBB2 (a member of EGFR family) in the context of miR-7 expression in human heart failure and in mice post-TAC (Transverse Aortic Constriction). To directly determine the role of miR-7 in the heart, we generated transgenic (Tg) mice with cardiomyocyte-specific overexpression of miR-7 (miR-7 Tg). miR-7 Tg mice are characterized by marked loss in ERBB2 expression compared to their wildtype littermate controls. Also, miR-7 Tg mice have age-dependent deterioration in cardiac dysfunction and is associated with dilation as measured by echocardiography (3 months - 60% FS, 6 month -52% FS and 12 months - 24%FS) and yet, they survive over 18 months as assessed by Kaplan-Meier curves. To investigate whether pathological stress would accelerate the deterioration in cardiac function, miR-7 Tg mice were subjected to TAC for two weeks. In contrast to the wild type littermates that showed significant hypertrophic response, miR-7 Tg mice have accelerated cardiac dysfunction and dilation following two weeks of TAC. Histological analysis shows increased collagen deposition in miR-7 Tg mice which is further accelerated following after TAC compared to their sham controls. These observations suggest that ERBB2 expression in the cardiomyocytes may play a critical role in delaying the pro-fibrotic response post-TAC by supporting an adaptive hypertrophic response in response to stress. Our study will discuss the mechanisms of increased fibrosis observed in miR-7 Tg mice subjected to TAC.

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Cardiac expression of microRNA-7 is associated with adverse cardiac remodeling

Scientific Reports ◽

10.1038/s41598-021-00778-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Manveen K. Gupta ◽

Anita Sahu ◽

Yu Sun ◽

Maradumane L. Mohan ◽

Avinash Kumar ◽

...

Keyword(s):

Growth Factor Receptor ◽

Significant Loss ◽

Transverse Aortic Constriction ◽

Cardiac Physiology ◽

Aortic Constriction ◽

Hypertrophic Response ◽

Erbb2 Expression ◽

Physiological Cardiac Hypertrophy ◽

Epidermal Growth

AbstractAlthough microRNA-7 (miRNA-7) is known to regulate proliferation of cancer cells by targeting Epidermal growth factor receptor (EGFR/ERBB) family, less is known about its role in cardiac physiology. Transgenic (Tg) mouse with cardiomyocyte-specific overexpression of miRNA-7 was generated to determine its role in cardiac physiology and pathology. Echocardiography on the miRNA-7 Tg mice showed cardiac dilation instead of age-associated physiological cardiac hypertrophy observed in non-Tg control mice. Subjecting miRNA-7 Tg mice to transverse aortic constriction (TAC) resulted in cardiac dilation associated with increased fibrosis bypassing the adaptive cardiac hypertrophic response to TAC. miRNA-7 expression in cardiomyocytes resulted in significant loss of ERBB2 expression with no changes in ERBB1 (EGFR). Cardiac proteomics in the miRNA-7 Tg mice showed significant reduction in mitochondrial membrane structural proteins compared to NTg reflecting role of miRNA-7 beyond the regulation of EGFR/ERRB in mediating cardiac dilation. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized rounded mitochondria that was associated with mitochondrial dysfunction. These findings show that expression of miRNA-7 in the cardiomyocytes results in cardiac dilation instead of adaptive hypertrophic response during aging or to TAC providing insights on yet to be understood role of miRNA-7 in cardiac function.

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Molecular Targeting Therapy against EGFR Family in Breast Cancer: Progress and Future Potentials

Cancers ◽

10.3390/cancers11121826 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1826 ◽

Cited By ~ 22

Author(s):

Amaia Eleonora Maennling ◽

Mehmet Kemal Tur ◽

Marcus Niebert ◽

Torsten Klockenbring ◽

Felix Zeppernick ◽

...

Keyword(s):

Breast Cancer ◽

Tyrosine Kinases ◽

Cell Cycle Progression ◽

Growth Factor Receptor ◽

Targeting Therapy ◽

Pancreas Head ◽

Downstream Signaling ◽

Strong Stimulation ◽

Epidermal Growth ◽

Egfr Family

The epidermal growth factor receptor (EGFR) family contains four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) and 13 secreted polypeptide ligands. EGFRs are overexpressed in many solid tumors, including breast, pancreas, head-and-neck, prostate, ovarian, renal, colon, and non-small-cell lung cancer. Such overexpression produces strong stimulation of downstream signaling pathways, which induce cell growth, cell differentiation, cell cycle progression, angiogenesis, cell motility and blocking of apoptosis.The high expression and/or functional activation of EGFRs correlates with the pathogenesis and progression of several cancers, which make them attractive targets for both diagnosis and therapy. Several approaches have been developed to target these receptors and/or the EGFR modulated effects in cancer cells. Most approaches include the development of anti-EGFRs antibodies and/or small-molecule EGFR inhibitors. This review presents the state-of-the-art and future prospects of targeting EGFRs to treat breast cancer.

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Faculty Opinions recommendation of Nonmuscle myosin II is required for internalization of the epidermal growth factor receptor and modulation of downstream signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717955023.793460364 ◽

2012 ◽

Author(s):

Thomas Egelhoff

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Myosin Ii ◽

Growth Factor Receptor ◽

Nonmuscle Myosin ◽

Downstream Signaling ◽

Nonmuscle Myosin Ii ◽

Epidermal Growth

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Differential effects of epidermal growth factor receptor inhibitors in a single patient with neuropathic pain

BMJ Case Reports ◽

10.1136/bcr-2020-239385 ◽

2021 ◽

Vol 14 (3) ◽

pp. e239385

Author(s):

Marte Grønlie Cameron ◽

Christian Kersten

Keyword(s):

Epidermal Growth Factor Receptor ◽

Neuropathic Pain ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Growth Factor Receptor ◽

Differential Effects ◽

Pain Scores ◽

Medical Need ◽

Epidermal Growth ◽

Egfr Family

Neuropathic pain (NP) represents an unmet medical need, where analgesic responses to different epidermal growth factor receptor inhibitors (EGFR-Is) have been described. The human EGFR family of receptors consists of four members (human epidermal growth factor receptor, HER 1–4), signalling via different homodimer and heterodimer combinations. A 52-year-old man was treated with the EGFR-I cetuximab in a trial of severe NP. Pain scores decreased dramatically after blinded cetuximab, but not after placebo. On pain recurrence after the trial, he was prescribed the oral EGFR-Is erlotinib, gefitinib, and lapatinib without relief. However, treatment with the pan-HER-inhibitor afatinib was effective. After 4 years on afatinib, pain control remains excellent with manageable side effects. This is the first reported observation of differential effects of EGFR-Is on NP in the same patient and the first report describing NP relief with afatinib. Further understanding of the underlying pathophysiology could lead to development of EGFR-Is specifically targeting NP.

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The Motile Breast Cancer Phenotype Roles of Proteoglycans/Glycosaminoglycans

BioMed Research International ◽

10.1155/2014/124321 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 16

Author(s):

Dragana Nikitovic ◽

Katerina Kouvidi ◽

Kallirroi Voudouri ◽

Aikaterini Berdiaki ◽

Evgenia Karousou ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Growth Factor Receptor ◽

Downstream Signaling ◽

Insulin Growth Factor ◽

Cancer Pathogenesis ◽

Cellular Mediators ◽

Epidermal Growth ◽

Cancer Phenotype ◽

Insulin Growth Factor Receptor

The consecutive stages of cancer growth and dissemination are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Importantly, cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycan (PG) content and distribution are markedly altered during tumor pathogenesis and progression. GAGs and PGs perform multiple functions in specific stages of the metastatic cascade due to their defined structure and ability to interact with both ligands and receptors regulating cancer pathogenesis. Thus, GAGs/PGs may modulate downstream signaling of key cellular mediators including insulin growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), estrogen receptors (ERs), or Wnt members. In the present review we will focus on breast cancer motility in correlation with their GAG/PG content and critically discuss mechanisms involved. Furthermore, new approaches involving GAGs/PGs as potential prognostic/diagnostic markers or as therapeutic agents for cancer-related pathologies are being proposed.

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Mechanical stresses induce paracrine β-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor

Clinical Science ◽

10.1042/cs20180486 ◽

2018 ◽

Vol 132 (16) ◽

pp. 1855-1874 ◽

Cited By ~ 2

Author(s):

Yang Li ◽

Xiaoyi Zhang ◽

Lu Li ◽

Xiang Wang ◽

Zhidan Chen ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cardiac Dysfunction ◽

Cardiac Fibroblasts ◽

Growth Factor Receptor ◽

Pressure Overload ◽

Dependent Manner ◽

Epidermal Growth ◽

High Level

By employing a proteomic analysis on supernatant of mechanically stretched cardiomyocytes, we found that stretch induced a significantly high level of β-2 microglobulin (β2M), a non-glycosylated protein, which is related to inflammatory diseases but rarely known in cardiovascular diseases. The present data showed that serum β2M level was increased in patients with hypertension and further increased in patients with chronic heart failure (HF) as compared with control group, and the high level of serum β2M level correlated to cardiac dysfunction in these patients. In pressure overload mice model by transverse aortic constriction (TAC), β2M levels in serum and heart tissue increased progressively in a time-dependent manner. Exogenous β2M showed pro-fibrotic effects in cultured cardiac fibroblasts but few effects in cardiomyocytes. Adeno-associated virus 9 (AAV9)-mediated knockdown of β2M significantly reduced cardiac β2M level and inhibited myocardial fibrosis and cardiac dysfunction but not cardiac hypertrophy at 4 weeks after TAC. In vitro, mechanical stretch induced the rapid secretion of β2M mainly from cardiomyocytes by activation of extracellular-regulated protein kinase (ERK). Conditional medium (CM) from mechanically stretched cardiomyocytes activated cultured cardiac fibroblasts, and the effect was partly abolished by CM from β2M-knockdown cardiomyocytes. In vivo, knockdown of β2M inhibited the increase in phosphorylation of epidermal growth factor receptor (EGFR) induced by TAC. In cultured cardiac fibroblasts, inhibition of EGFR significantly attenuated the β2M-induced the activation of EGFR and pro-fibrotic responses. The present study suggests that β2M is a paracrine pro-fibrotic mediator and associated with cardiac dysfunction in response to pressure overload.

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