Journal of Clinical Medicine

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Open AccessEditorial

Acknowledgement to Reviewers of Journal of Clinical Medicine in 2015

by Journal of Clinical Medicine Editorial Office

J. Clin. Med. 2016, 5(1), 12; https://doi.org/10.3390/jcm5010012 - 21 Jan 2016

Viewed by 3006

The editors of Journal of Clinical Medicine would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. [...] Full article

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Open AccessReview

Epithelial-Mesenchymal Transition (EMT) and Regulation of EMT Factors by Steroid Nuclear Receptors in Breast Cancer: A Review and in Silico Investigation

by Ioannis A. Voutsadakis

J. Clin. Med. 2016, 5(1), 11; https://doi.org/10.3390/jcm5010011 - 19 Jan 2016

Cited by 75 | Viewed by 8965

Abstract

Steroid Nuclear Receptors (SNRs) are transcription factors of the nuclear receptor super-family. Estrogen Receptor (ERα) is the best-studied and has a seminal role in the clinic both as a prognostic marker but also as a predictor of response to anti-estrogenic therapies. Progesterone Receptor [...] Read more.

Steroid Nuclear Receptors (SNRs) are transcription factors of the nuclear receptor super-family. Estrogen Receptor (ERα) is the best-studied and has a seminal role in the clinic both as a prognostic marker but also as a predictor of response to anti-estrogenic therapies. Progesterone Receptor (PR) is also used in the clinic but with a more debatable prognostic role and the role of the four other SNRs, ERβ, Androgen Receptor (AR), Glucocorticoid Receptor (GR) and Mineralocorticoid Receptor (MR), is starting only to be appreciated. ERα, but also to a certain degree the other SNRs, have been reported to be involved in virtually every cancer-enabling process, both promoting and impeding carcinogenesis. Epithelial-Mesenchymal Transition (EMT) and the reverse Mesenchymal Epithelial Transition (MET) are such carcinogenesis-enabling processes with important roles in invasion and metastasis initiation but also establishment of tumor in the metastatic site. EMT is governed by several signal transduction pathways culminating in core transcription factors of the process, such as Snail, Slug, ZEB1 and ZEB2, and Twist, among others. This paper will discuss direct regulation of these core transcription factors by SNRs in breast cancer. Interrogation of publicly available databases for binding sites of SNRs on promoters of core EMT factors will also be included in an attempt to fill gaps where other experimental data are not available. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)

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Open AccessArticle

Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow

by Ayaka Okamoto, Tomohiro Asai, Sho Ryu, Hidenori Ando, Noriyuki Maeda, Takehisa Dewa and Naoto Oku

J. Clin. Med. 2016, 5(1), 10; https://doi.org/10.3390/jcm5010010 - 19 Jan 2016

Cited by 17 | Viewed by 5718

Abstract

Genetic therapy using microRNA-499 (miR-499) was combined with chemotherapy for the advanced treatment of cancer. Our previous study showed that miR-499 suppressed tumor growth through the inhibition of vascular endothelial growth factor (VEGF) production and subsequent angiogenesis. In the present study, we focused [...] Read more.

Genetic therapy using microRNA-499 (miR-499) was combined with chemotherapy for the advanced treatment of cancer. Our previous study showed that miR-499 suppressed tumor growth through the inhibition of vascular endothelial growth factor (VEGF) production and subsequent angiogenesis. In the present study, we focused on blood flow in tumors treated with miR499, since some angiogenic vessels are known to lack blood flow. Tetraethylenepentamine-based polycation liposomes (TEPA-PCL) were prepared and modified with Ala-Pro-Arg-Pro-Gly peptide (APRPG) for targeted delivery of miR-499 (APRPG-miR-499) to angiogenic vessels and tumor cells. The tumor blood flow was significantly improved, so-called normalized, after systemic administration of APRPG-miR-499 to Colon 26 NL-17 carcinoma–bearing mice. In addition, the accumulation of doxorubicin (DOX) in the tumors was increased by pre-treatment with APRPG-miR-499. Moreover, the combination therapy of APRPG-miR-499 and DOX resulted in significant suppression of the tumors. Taken together, our present data indicate that miR-499 delivered with APRPG-modified-TEPA-PCL normalized tumor vessels, resulting in enhancement of intratumoral accumulation of DOX. Our findings suggest that APRPG-miR-499 may be a therapeutic, or a combination therapeutic, candidate for cancer treatment. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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miR-499-mediated improvement of blood flow in tumor blood vessels. Colon 26 NL-17 cells were subcutaneously implanted into the left posterior flank of BALB/c mice. APRPG-miR-499 or APRPG-miCont (2 mg/kg as miRNA) were administered intravenously seven days after the implantation. Perfused vessels were labeled by intravenous injection of biotin-conjugated Lycopersicon esculentum Lectin at 96 h after the lipoplex injection. The tumor vessels were fixed by reflux flow with 1% paraformaldehyde. After the solid tumors had been dissected, 10-μm frozen sections were prepared. CD31 of the vasculature was immunostained with FITC. Biotin-conjugated Lycopersicon esculentum Lectin was labeled with Streptavidin-Alexa Fluor® 594. Green indicates vasculature, red indicates vessels with blood flow. Yellow color indicates areas of double-stained vessels. (A) Confocal images are shown. Scale bars indicate 100 µm; (B) Percent lectin+CD31+ double-positive area/total CD31+ area was determined to assess perfusion efficiency of the tumor vasculature. Data are presented as percent ratio of merged area/CD31+ area. Asterisks indicate significant differences (** p < 0.01 vs. control, ### p < 0.001 vs. APRPG-miCont). Full article ">Figure 2
Improvement of DOX accumulation in tumors treated with miR-499. Colon 26 NL-17 cells were subcutaneously implanted into the left posterior flank of BALB/c mice. APRPG-miR-499 or APRPG-miCont were administered intravenously seven days after implantation. Four days after the lipoplex injection, DOX was administered intravenously. Three hours after DOX injection, tumor tissues were excised. The tumors were homogenized with ShakeMan2 and then centrifuged. DOX accumulation was quantified by measuring the fluorescence of DOX (Ex. 470 nm, Em. 590 nm). Asterisks indicate significant differences (* p < 0.05). Full article ">Figure 3
Combination therapy with miR-499 and DOX. Colon 26 NL-17 cells were subcutaneously implanted into the left posterior flank of BALB/c mice. APRPG-miR-499 was administered intravenously when the tumor volume had reached 50 mm3. In the case of combination therapy, DOX (5 mg/kg) was intravenously injected via a tail vein at four days after the lipoplex injection. The tumor size (A,B); and body weight (C,D) of each mouse were monitored daily from one day before lipoplex injection. Asterisks indicate significant differences (* p < 0.05, ** p < 0.01, *** p < 0.001). N.S. means no significant difference. Full article ">Figure 4
Associations of signaling pathways and miR-499. The blue arrows indicate upregulation. The red symbols mean inhibition. Full article ">

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Open AccessFeature PaperReview

Controversies over the Epithelial-to-Mesenchymal Transition in Liver Fibrosis

by Kojiro Taura, Keiko Iwaisako, Etsuro Hatano and Shinji Uemoto

J. Clin. Med. 2016, 5(1), 9; https://doi.org/10.3390/jcm5010009 - 14 Jan 2016

Cited by 42 | Viewed by 5427

Abstract

Liver fibrosis is a universal consequence of chronic liver diseases. It is accompanied by activation of collagen-producing myofibroblasts, resulting in excessive deposition of extracellular matrix. The origin of myofibroblasts in the fibrotic liver has not been completely resolved and remains a matter of [...] Read more.

Liver fibrosis is a universal consequence of chronic liver diseases. It is accompanied by activation of collagen-producing myofibroblasts, resulting in excessive deposition of extracellular matrix. The origin of myofibroblasts in the fibrotic liver has not been completely resolved and remains a matter of debate. Recently, the epithelial-to-mesenchymal transition (EMT) was proposed as one of the mechanisms that give rise to collagen-producing myofibroblasts in liver fibrosis. However, subsequent studies contradicted this hypothesis, and the EMT theory has become one of the most controversial and debatable issues in the field of liver fibrosis research. This review will summarize the existing literature on EMT in liver fibrosis and will analyze the causes for the contradictory results to draw a reasonable conclusion based on current knowledge in the field. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)

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Open AccessFeature PaperReview

MicroRNA Regulation of Epithelial to Mesenchymal Transition

by Mohammed L. Abba, Nitin Patil, Jörg Hendrik Leupold and Heike Allgayer

J. Clin. Med. 2016, 5(1), 8; https://doi.org/10.3390/jcm5010008 - 14 Jan 2016

Cited by 101 | Viewed by 10676

Abstract

Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis. In addition to its physiological role in tissue repair and wound healing, EMT contributes to chemo resistance, metastatic dissemination and fibrosis, [...] Read more.

Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis. In addition to its physiological role in tissue repair and wound healing, EMT contributes to chemo resistance, metastatic dissemination and fibrosis, amongst others. Classically, the morphological change from epithelial to mesenchymal phenotype is characterized by the appearance or loss of a group of proteins which have come to be recognized as markers of the EMT process. As with all proteins, these molecules are controlled at the transcriptional and translational level by transcription factors and microRNAs, respectively. A group of developmental transcription factors form the backbone of the EMT cascade and a large body of evidence shows that microRNAs are heavily involved in the successful coordination of mesenchymal transformation and vice versa, either by suppressing the expression of different groups of transcription factors, or otherwise acting as their functional mediators in orchestrating EMT. This article dissects the contribution of microRNAs to EMT and analyzes the molecular basis for their roles in this cellular process. Here, we emphasize their interaction with core transcription factors like the zinc finger enhancer (E)-box binding homeobox (ZEB), Snail and Twist families as well as some pluripotency transcription factors. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)

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Open AccessReview

Reversible Human TGF-β Signal Shifting between Tumor Suppression and Fibro-Carcinogenesis: Implications of Smad Phospho-Isoforms for Hepatic Epithelial-Mesenchymal Transitions

by Katsunori Yoshida, Miki Murata, Takashi Yamaguchi, Koichi Matsuzaki and Kazuichi Okazaki

J. Clin. Med. 2016, 5(1), 7; https://doi.org/10.3390/jcm5010007 - 12 Jan 2016

Cited by 40 | Viewed by 7738

Abstract

Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate [...] Read more.

Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate linker regions connecting Mad homology domains, act as the intracellular mediators of the TGF-β signal transduction pathway. As the TGF-β receptors, c-Jun N-terminal kinase and cyclin-dependent kinase, differentially phosphorylate Smad2/3, we have generated numerous antibodies against linker (L) and C-terminal (C) phosphorylation sites in Smad2/3 and identified four types of phosphorylated forms: cytostatic COOH-terminally-phosphorylated Smad3 (pSmad3C), mitogenic pSmad3L (Ser-213) signaling, fibrogenic pSmad2L (Ser-245/250/255)/C signaling and migratory pSmad2/3L (Thr-220/179)/C signaling. After acute liver injury, TGF-β upregulates pSmad3C signaling and terminates pSmad3L (Ser-213)-mediated hepatocyte proliferation. TGF-β and pro-inflammatory cytokines cooperatively enhance collagen synthesis by upregulating pSmad2L (Thr-220)/C and pSmad3L (Thr-179)/C pathways in activated hepatic stellate cells. During chronic liver injuries, hepatocytes persistently affected by TGF-β and pro-inflammatory cytokines eventually become pre-neoplastic hepatocytes. Both myofibroblasts and pre-neoplastic hepatocyte exhibit the same carcinogenic (mitogenic) pSmad3L (Ser-213) and fibrogenic pSmad2L (Ser-245/250/255)/C signaling, with acquisition of fibro-carcinogenic properties and increasing risk of hepatocellular carcinoma (HCC). Firstly, we review phospho-Smad-isoform signalings in epithelial and mesenchymal cells in physiological and pathological conditions and then consider Smad linker phosphorylation as a potential target for pathological EMT during human fibro-carcinogenesis, because human Smad phospho-isoform signals can reverse from fibro-carcinogenesis to tumor-suppression in a process of MET after therapy. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)

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Liver regeneration-related EMT and phospho-Smad signaling in acute liver disease. (A) Quiescent hepatic stellate cells (HSC) are characterized by retinoid droplets in the cytoplasm. Acute liver injury caused HSC activation and hepatocyte damage, necrosis and EMT. Activated HSC move from the space of Disse to sites of damage where the activated HSC contribute to tissue repair by producing large amounts of collagen. HSC also play an important role in secreting TGF-β. (B) Catalytically-active TβRI phosphorylates COOH-tail serine residues of Smad2 and Smad3. Both pSmad2C and pSmad3C are localized in the nuclei of hepatocytes and mesenchymal cells in acute injured liver. After binding with Smad4, pSmad2/3C translocate with Smad4 to the nucleus and bind to the collagen promoter. pSmad2/3C stimulate extracellular matrix (ECM) deposition and suppress cell growth by c-Myc inhibition. However, Smad7 induced by the pSmad3L/C signal terminates the fibrogenic phospho-Smad signaling. This negative feedback mechanism of the fibrogenic TGF-β/CK signal results in a transient collagen synthesis in the activated HSC, which may thus contribute to tissue repair. Full article ">Figure 2
Liver fibro-carcinogenesis-related EMT and phospho-Smad signaling during chronic liver disease. (A) Prolonged exposure to chronic injury; HSC undergo constitutive activation to become myofibroblasts (MFB)-like cells, which persistently induce deposition of ECM and liver fibrosis. Continuous insults will shift EMT-like cells to complete EMT and pre-neoplastic hepatocytes. (B) During chronic liver injury, pro-inflammatory cytokines (CK), such as TNF-α activate JNK, result in phosphorylation of both Smad2L and Smad3L, both in MFB and pre-neoplastic hepatocyte. P-Smad3L translocates with Smad4 to the nucleus and binds the PAI-1 promoter. After COOH-tail phosphorylation of cytoplasmic pSmad2L by TβRI, pSmad2L/C translocates to the nucleus. Both pSmad2L/C and pSmad3L stimulates PAI-1 transcription and ECM deposition, while they suppress the pSmad3C-mediated tumor suppressive pathway. Pre-neoplastic hepatocytes exhibit the same oncogenic (mitogenic) pSmad3L and fibrogenic pSmad2L signaling as MFB, thereby accelerating liver fibrosis and increasing the risk of HCC. In contrast to Smad7 induction in HSC via the pSmad3C pathway, pSmad3L cannot induce Smad7 in MFB and pre-neoplastic hepatocytes (left). Under a low level of Smad7, the fibrogenic phospho-Smad signaling can constitutively promote ECM deposition by MFB, which may eventually develop into accelerated liver fibro-carcinogenesis. Full article ">Figure 3
Phosphorylated Smad2/3 signaling fibro-carcinogenesis. As human hepatitis virus-related chronic liver diseases progress, chronic inflammation and hepatitis virus additively shift hepatocytic Smad phospho-isoform signaling from tumor-suppressive pSmad3C to the fibro-carcinogenic pSmad3L and pSmad2L/C pathway. Anti-viral therapy can reverse phospho-Smad signaling from fibro-carcinogenesis to tumor suppression. Type 2 EMT promotes liver fibrosis induced by chronic inflammation. Type 3 EMT exacerbates the HCC phenotype by upregulating invasive and metastatic potential. Full article ">

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Open AccessReview

Emerging Transcriptional Mechanisms in the Regulation of Epithelial to Mesenchymal Transition and Cellular Plasticity in the Kidney

by Letizia De Chiara and John Crean

J. Clin. Med. 2016, 5(1), 6; https://doi.org/10.3390/jcm5010006 - 12 Jan 2016

Cited by 19 | Viewed by 6458

Abstract

Notwithstanding controversies over the role of epithelial to mesenchymal transition in the pathogenesis of renal disease, the last decade has witnessed a revolution in our understanding of the regulation of renal cell plasticity. Significant parallels undoubtedly exist between ontogenic processes and the initiation [...] Read more.

Notwithstanding controversies over the role of epithelial to mesenchymal transition in the pathogenesis of renal disease, the last decade has witnessed a revolution in our understanding of the regulation of renal cell plasticity. Significant parallels undoubtedly exist between ontogenic processes and the initiation and propagation of damage in the diseased kidney as evidenced by the reactivation of developmental programmes of gene expression, in particular with respect to TGFβ superfamily signaling. Indeed, multiple signaling pathways converge on a complex transcriptional regulatory nexus that additionally involves epigenetic activator and repressor mechanisms and microRNA regulatory networks that control renal cell plasticity. It is becoming increasingly apparent that differentiated cells can acquire an undifferentiated state akin to “stemness” which is leading us towards new models of complex cell behaviors and interactions. Here we discuss the latest findings that delineate new and novel interactions between this transcriptional regulatory network and highlight a hitherto poorly recognized role for the Polycomb Repressive Complex (PRC2) in the regulation of renal cell plasticity. A comprehensive understanding of how external stimuli interact with the epigenetic control of gene expression, in normal and diseased contexts, establishes a new therapeutic paradigm to promote the resolution of renal injury and regression of fibrosis. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)

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Epithelial to Mesenchymal transition. During Epithelial to Mesenchymal transition (EMT), epithelial cells lose their organized phenotype and gain a scattered mesenchymal phenotype. This transition can be caused by various growth factors and is characterized by loss of polarization, tight junctional integrity, and E-Cadherin expression. The epithelial cells undergoing EMT acquire a fibroblastic appearance, increased motility and de novo expression of SNAI1, Vimentin, α-SMA, and N-Cadherin. Full article ">Figure 2
The role of intermediate “hybrid” cells during kidney regeneration. Following acute injury, renal epithelial cells are able to repair and recover their functionality. During this process, the renal epithelial cells undergo a process of profound plasticity in which they acquire a less epithelial phenotype and gain some mesenchymal characteristic, such as vimentin expression. These partially “reprogrammed” cells are able to proliferate and repair the damage. Full article ">Figure 3
From mesenchymal to epithelial fate: routes to plasticity. Mesenchymal cells are characterized by a fibroblastic spindle-like phenotype. These cells do not express E-Cadherin and they have a low but detectable level of SNAI1 and EZH2. During transition to plasticity caused by forced expression of the 4 Yamanaka factors, these cells undergo a process of profound remodeling and they acquire the expression of both EZH2 and SNAI1. Once they become highly plastic and responsive, at a relatively low ratio, they acquire a fully pluripotent state (A). It is interesting to note that a similar process take places when human mesangial cells are forced to acquire a more plastic phenotype. While this process has something in common with fibrosis, the cells do not become fibrotic but they only acquire an enhanced plasticity. At this critical tipping point if these cells are grown in the right environment and with appropriate stimuli, they acquire epithelial characteristics and de novo expression of Zonula Occludens (ZO)-1 (B). This process is very dynamic and can be blocked or reversed. Full article ">Figure 4
Working model. The balance between Epithelial and Mesenchymal phenotype controls various processes during embryogenesis, development, diseases, and acquisition of pluripotency. By better understanding how this process is tuned-in and regulated, we may be able to stop the progression and initiate the regression of multiple fibrotic disease, such as the one affecting the kidney. Full article ">

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Open AccessReview

An Overview of Insulin Pumps and Glucose Sensors for the Generalist

by Brooke H. McAdams and Ali A. Rizvi

J. Clin. Med. 2016, 5(1), 5; https://doi.org/10.3390/jcm5010005 - 4 Jan 2016

Cited by 90 | Viewed by 28878

Abstract

Continuous subcutaneous insulin, or the insulin pump, has gained popularity and sophistication as a near-physiologic programmable method of insulin delivery that is flexible and lifestyle-friendly. The introduction of continuous monitoring with glucose sensors provides unprecedented access to, and prediction of, a patient’s blood [...] Read more.

Continuous subcutaneous insulin, or the insulin pump, has gained popularity and sophistication as a near-physiologic programmable method of insulin delivery that is flexible and lifestyle-friendly. The introduction of continuous monitoring with glucose sensors provides unprecedented access to, and prediction of, a patient’s blood glucose levels. Efforts are underway to integrate the two technologies, from “sensor-augmented” and “sensor-driven” pumps to a fully-automated and independent sensing-and-delivery system. Implantable pumps and an early-phase “bionic pancreas” are also in active development. Fine-tuned “pancreas replacement” promises to be one of the many avenues that offers hope for individuals suffering from diabetes. Although endocrinologists and diabetes specialists will continue to maintain expertise in this field, it behooves the primary care physician to have a working knowledge of insulin pumps and sensors to ensure optimal clinical care and decision-making for their patients. Full article

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Open AccessReview

The Effect of Marine Derived n-3 Fatty Acids on Adipose Tissue Metabolism and Function

by Marijana Todorčević and Leanne Hodson

J. Clin. Med. 2016, 5(1), 3; https://doi.org/10.3390/jcm5010003 - 31 Dec 2015

Cited by 65 | Viewed by 8174

Abstract

Adipose tissue function is key determinant of metabolic health, with specific nutrients being suggested to play a role in tissue metabolism. One such group of nutrients are the n-3 fatty acids, specifically eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; [...] Read more.

Adipose tissue function is key determinant of metabolic health, with specific nutrients being suggested to play a role in tissue metabolism. One such group of nutrients are the n-3 fatty acids, specifically eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Results from studies where human, animal and cellular models have been utilised to investigate the effects of EPA and/or DHA on white adipose tissue/adipocytes suggest anti-obesity and anti-inflammatory effects. We review here evidence for these effects, specifically focusing on studies that provide some insight into metabolic pathways or processes. Of note, limited work has been undertaken investigating the effects of EPA and DHA on white adipose tissue in humans whilst more work has been undertaken using animal and cellular models. Taken together it would appear that EPA and DHA have a positive effect on lowering lipogenesis, increasing lipolysis and decreasing inflammation, all of which would be beneficial for adipose tissue biology. What remains to be elucidated is the duration and dose required to see a favourable effect of EPA and DHA in vivo in humans, across a range of adiposity. Full article

(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Disease)

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Open AccessReview

Pathogenesis of Type 2 Epithelial to Mesenchymal Transition (EMT) in Renal and Hepatic Fibrosis

by Anusha H. Tennakoon, Takeshi Izawa, Mitsuru Kuwamura and Jyoji Yamate

J. Clin. Med. 2016, 5(1), 4; https://doi.org/10.3390/jcm5010004 - 30 Dec 2015

Cited by 41 | Viewed by 11721

Abstract

Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also [...] Read more.

Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also occurs in injured hepatocytes and hepatic progenitor cells (HPCs), as well as ductular reaction-related bile epithelia. Interestingly, the ductular reaction contributes partly to hepatocarcinogenesis of HPCs, and further, regenerating cholangiocytes after injury may be derived from hepatic stellate cells via mesenchymal to epithelia transition, a reverse phenomenon of type 2 EMT. Possible pathogenesis of type 2 EMT and its differences between renal and hepatic fibrosis are reviewed based on our experimental data. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)

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Open AccessReview

MicroRNA Regulation of Human Breast Cancer Stem Cells

by Yohei Shimono, Junko Mukohyama, Shun-ichi Nakamura and Hironobu Minami

J. Clin. Med. 2016, 5(1), 2; https://doi.org/10.3390/jcm5010002 - 25 Dec 2015

Cited by 79 | Viewed by 11401

Abstract

MicroRNAs (miRNAs) are involved in virtually all biological processes, including stem cell maintenance, differentiation, and development. The dysregulation of miRNAs is associated with many human diseases including cancer. We have identified a set of miRNAs differentially expressed between human breast cancer stem cells [...] Read more.

MicroRNAs (miRNAs) are involved in virtually all biological processes, including stem cell maintenance, differentiation, and development. The dysregulation of miRNAs is associated with many human diseases including cancer. We have identified a set of miRNAs differentially expressed between human breast cancer stem cells (CSCs) and non-tumorigenic cancer cells. In addition, these miRNAs are similarly upregulated or downregulated in normal mammary stem/progenitor cells. In this review, we mainly describe the miRNAs that are dysregulated in human breast CSCs directly isolated from clinical specimens. The miRNAs and their clusters, such as the miR-200 clusters, miR-183 cluster, miR-221-222 cluster, let-7, miR-142 and miR-214, target the genes and pathways important for stem cell maintenance, such as the self-renewal gene BMI1, apoptosis, Wnt signaling, Notch signaling, and epithelial-to-mesenchymal transition. In addition, the current evidence shows that metastatic breast CSCs acquire a phenotype that is different from the CSCs in a primary site. Thus, clarifying the miRNA regulation of the metastatic breast CSCs will further advance our understanding of the roles of human breast CSCs in tumor progression. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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A schematic representation of the miRNA clusters dysregulated in human breast CSCs. The miRNAs sharing the same seed sequence (nucleotides from two to seven) are marked by the same color. The mammalian miR-200 clusters are expressed as two separate polycistronic pri-miRNA transcripts. The miRNAs coded in the miR-200b-200a-429, miR-200c-141 and miR-183-96-182 clusters are downregulated, and those in the miR-221-222 cluster are upregulated in the human breast CSCs. The arrows indicate the direction of the pri-miRNA transcription. Full article ">Figure 2
Regulation of cell cycle, apoptosis, and senescence by self-renewal factor Bmi1. Bmi1, a component of PRC1, is involved in the stem cell maintenance in multiple tissues and organs. PRC1 suppresses the Ink4a locus that encodes the p16Ink4a and the p19Arf genes through the specific biochemical histone modifications, such as the trimethylation of the H3-K27 (H3K27me3) and the ubiquitination of H2A-K119 (H2AK119Ub). The chromodomain of CBX binds to H3K27me3 and RING1 deposits monoubiquitin on H2AK119. In the absence of p16Ink4a, the cyclin D/Cdk4/6 complex can phosphorylate RB, allowing the E2F-dependent transcription which leads to cell cycle progression. In the absence of p19Arf, MDM2-mediated p53 degradation causes low p53 levels, thus preventing cell cycle arrest and apoptosis. In addition, the gradual accumulation of p16Ink4a expression during physiological aging implicates that p16Ink4a is involved in the regulation of senescence. Full article ">Figure 3
Targeting of the genes and pathways for stem cell maintenance by miR-200 family miRNAs. Expression of the miR-200 family miRNAs is downregulated in the breast CSCs and normal mammary stem/progenitor cells, and is upregulated in the more differentiated counterparts. The miR-200 family miRNAs are involved in the regulation stem cell functions by targeting the genes and pathways important for stem cell maintenance, such as self-renewal factor Bmi-1, the apoptosis signaling pathway, the canonical Wnt signaling pathway, EMT and the Notch signaling pathway. Full article ">Figure 4
Activation of the canonical Wnt signaling pathway by the breast CSC-specific miRNAs. The canonical Wnt signaling pathway is implicated in both stem cell self-renewal and cancer. The multiple miRNAs dysregulated in the breast CSCs, such as miR-142, miR-146, miR-200, and miR-141, cooperatively activate the Wnt signaling pathway by targeting or upregulating the expression of its components. The activation of the Wnt signaling pathway induces the transcription of the Wnt target genes, including miR-146 and miR-150. miR-150 enhances the proliferation of mammary epithelial cells. Upregulation of miR-146 further enhances the activity of the Wnt signaling pathway in a positive feedback manner. Full article ">

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Open AccessReview

Epithelial–Mesenchymal Transitions during Neural Crest and Somite Development

by Chaya Kalcheim

J. Clin. Med. 2016, 5(1), 1; https://doi.org/10.3390/jcm5010001 - 25 Dec 2015

Cited by 31 | Viewed by 8147

Abstract

Epithelial-to-mesenchymal transition (EMT) is a central process during embryonic development that affects selected progenitor cells of all three germ layers. In addition to driving the onset of cellular migrations and subsequent tissue morphogenesis, the dynamic conversions of epithelium into mesenchyme and vice-versa are [...] Read more.

Epithelial-to-mesenchymal transition (EMT) is a central process during embryonic development that affects selected progenitor cells of all three germ layers. In addition to driving the onset of cellular migrations and subsequent tissue morphogenesis, the dynamic conversions of epithelium into mesenchyme and vice-versa are intimately associated with the segregation of homogeneous precursors into distinct fates. The neural crest and somites, progenitors of the peripheral nervous system and of skeletal tissues, respectively, beautifully illustrate the significance of EMT to the above processes. Ongoing studies progressively elucidate the gene networks underlying EMT in each system, highlighting the similarities and differences between them. Knowledge of the mechanistic logic of this normal ontogenetic process should provide important insights to the understanding of pathological conditions such as cancer metastasis, which shares some common molecular themes. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)

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Epithelial to mesenchymal transition (EMT) of neural crest (NC) progenitors: Regulation and cellular dynamics. (A) The medial lip of the nascent dermomyotome (DM) controls the timing of NC delamination. In the early dorsal NT, prior to the onset of NC emigration, levels of Noggin are high thereby inhibiting the activity of BMP4 and NC delamination. The forming medial lip of the DM acts upon the dorsal NT via FGF8 and retinoic acid signaling to inhibit local noggin transcription thus relieving BMP4 which stimulates NC emigration. Scl, sclerotome; (B) Two possible models representing the dynamic dorsalward relocation of NC cells prior to emigration in association with fate restriction. In both models, the emigrating cells are largely fate-restricted. In the model on the left (spatial mechanism), a pattern reflecting the different fates is already apparent in the dorsal NT (color coding). In the model depicted on the right, fate restriction is assigned to a cell upon relocation to the dorsal midline area by a time-dependent mechanism. Abbreviations: DRG, dorsal root ganglia; M, melanocytes; RP, roof plate; SG, sympathetic ganglia; VR, Schwann cells along ventral root. Full article ">Figure 2
Successive stages in dermomyotome development at flank levels of the axis. Phase contrast images that illustrate: (A) T0, epithelial somite stage with the prospective dermomyotome (DM) highlighted by dashed lines; (B) T1, initial formation of the DM following mesenchymalization of the sclerotome (Scl). At this stage the pioneer (P) myoblasts bend underneath the nascent DM; (C) T2, the DM of a fully dissociated somite in which the primary myotome (M) is well differentiated. Note the well defined medial and lateral edges (DML and VLL, respectively); (D) T3, the DM dissociates into dermis except for the DML and VLL which still remain epithelial (demarcated by dashed lines). See text for precise stages. Abbreviations, DRG, dorsal root ganglion, NT, neural tube. Bar = (A) 8 μM; (B) 15 μM; (C) 22 μM; and (D) 80 μM. Full article ">

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J. Clin. Med., Volume 5, Issue 1 (January 2016) – 12 articles

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