scholarly journals Do DLX3 and CD271 Protect Human Keratinocytes from Squamous Tumor Development?

2019 ◽  
Vol 20 (14) ◽  
pp. 3541 ◽  
Author(s):  
Elisabetta Palazzo ◽  
Alessandra Marconi ◽  
Carlo Pincelli ◽  
Maria I. Morasso
Keyword(s):  
Tumor Development ◽  
Human Keratinocytes ◽  
Epidermal Differentiation ◽  
Trk Receptor ◽  
Neurotrophin 3 ◽  
Homeobox Transcription Factor ◽  
Epidermal Homeostasis ◽  
Transcription Regulators ◽  
And Function ◽  
Normal Epidermis

Well-regulated epidermal homeostasis depends on the function of different classes of factors, such as transcription regulators and receptors. Alterations in this homeostatic balance may lead to the development of cutaneous squamous tumorigenesis. The homeobox transcription factor DLX3 is determinant for a p53-dependent regulation of epidermal differentiation and modulates skin carcinogenesis. The maintenance of skin homeostasis also involves the action of neurotrophins (NTs) and their receptors, Trk and CD271. While Trk receptor overexpression is a hallmark of cancer, there are conflicting data on CD271 expression and function in cutaneous SCC (cSCC). Previous studies have reported NT receptors expression in head and neck SSC (HNSCC). We show that CD271 is expressed at low levels in primary cSCC cells and the number of CD271+ cells correlates with cell cohesion in SCC spheroids. In normal epidermis, CD271 is expressed in proliferative progenitor cells and DLX3 in terminally differentiated keratinocytes. Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) increase DLX3 expression. In the absence of a functional BDNF receptor TrkB in keratinocytes, we hypothesize that the BDNF-dependent DLX3 response could be mediated via CD271. Altogether, our results support a putative CD271-DLX3 connection in keratinocytes, which might be crucial to preventing squamous skin cancer.

scholarly journals Trichohyalin-like 1 protein plays a crucial role in proliferation and anti-apoptosis of normal human keratinocytes and squamous cell carcinoma cells

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Teruhiko Makino ◽  
Megumi Mizawa ◽  
Yoko Yoshihisa ◽  
Seiji Yamamoto ◽  
Yoshiaki Tabuchi ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Basal Layer ◽  
Human Keratinocytes ◽  
S100 Proteins ◽  
Epidermal Differentiation ◽  
Normal Human Keratinocytes ◽  
Normal Human ◽  
Normal Epidermis

Abstract Epidermal differentiation is a complex process that requires the regulated and sequential expression of various genes. Most fused-type S100 proteins are expressed in the granular layer and it is hypothesized that these proteins may be associated with cornification and barrier formation. We previously identified a member of the fused-type S100 proteins, Trichohyalin-like 1 (TCHHL1) protein. TCHHL1 is distributed in the basal layer of the normal epidermis. Furthermore, the expression is markedly increased in cancerous/non-cancerous skin samples with the hyperproliferation of keratinocytes. We herein examined the role of TCHHL1 in normal human keratinocytes (NHKs) and squamous cell carcinoma (SCC). The knockdown of TCHHL1 by transfection with TCHHL1 siRNA significantly inhibited proliferation and induced the early apoptosis of NHKs. In TCHHL1-knockdown NHKs, the level of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was markedly decreased. In addition, the slight inhibition of v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation and upregulation of forkhead box-containing protein O1(FOXO1), B-cell lymphoma2 (BCL2) and Bcl2-like protein 11 (BCL2L11) was observed. Skin-equivalent models built by TCHHL1-knockdown NHKs showed a markedly hypoplastic epidermis. These findings highlight that TCHHL1 plays an important role in homeostasis of the normal epidermis. TCHHL1 was expressed in the growing cells of cutaneous SCC; therefore, we next examined an association with the cell growth in HSC-1 cells (a human SCC line). In HSC-1 cells, the knockdown of TCHHL1 also suppressed cell proliferation and induced apoptosis. These cells showed an inhibition of phosphorylation of ERK1/2, AKT and signal transducers and activator of transcription 3, and the significant upregulation of FOXO1, BCL2, and BCL2L11. Accordingly, TCHHL1 is associated with survival of cutaneous SCC. In addition, we hypothesize that TCHHL1 may be a novel therapeutic target in cutaneous SCC.

scholarly journals Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma

2021 ◽  
Vol 22 (5) ◽  
pp. 2602
Author(s):  
Emilie Viennois ◽  
Benoit Chassaing
Keyword(s):  
Intestinal Inflammation ◽  
Tumor Development ◽  
Low Grade ◽  
Gastrointestinal Cancers ◽  
Cancer Initiation ◽  
And Function ◽  
The Impact ◽  
Chronic Intestinal Inflammation ◽  
Low Grade Inflammation ◽  
Intestinal Adenoma

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers’ impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host–microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.

scholarly journals Molecular and Pharmacological Characterization of the Interaction between Human Geranylgeranyltransferase Type I and Ras-Related Protein Rap1B

2021 ◽  
Vol 22 (5) ◽  
pp. 2501
Author(s):  
Sonja Hinz ◽  
Dominik Jung ◽  
Dorota Hauert ◽  
Hagen S. Bachmann
Keyword(s):  
Protein Function ◽  
Tumor Development ◽  
Cysteine Residue ◽  
Type I ◽  
Pharmacological Characterization ◽  
Anti Cancer ◽  
And Function ◽  
Caax Motif ◽  
Important Drug

Geranylgeranyltransferase type-I (GGTase-I) represents an important drug target since it contributes to the function of many proteins that are involved in tumor development and metastasis. This led to the development of GGTase-I inhibitors as anti-cancer drugs blocking the protein function and membrane association of e.g., Rap subfamilies that are involved in cell differentiation and cell growth. In the present study, we developed a new NanoBiT assay to monitor the interaction of human GGTase-I and its substrate Rap1B. Different Rap1B prenylation-deficient mutants (C181G, C181S, and ΔCQLL) were designed and investigated for their interaction with GGTase-I. While the Rap1B mutants C181G and C181S still exhibited interaction with human GGTase-I, mutant ΔCQLL, lacking the entire CAAX motif (defined by a cysteine residue, two aliphatic residues, and the C-terminal residue), showed reduced interaction. Moreover, a specific, peptidomimetic and competitive CAAX inhibitor was able to block the interaction of Rap1B with GGTase-I. Furthermore, activation of both Gαs-coupled human adenosine receptors, A2A (A2AAR) and A2B (A2BAR), increased the interaction between GGTase-I and Rap1B, probably representing a way to modulate prenylation and function of Rap1B. Thus, A2AAR and A2BAR antagonists might be promising candidates for therapeutic intervention for different types of cancer that overexpress Rap1B. Finally, the NanoBiT assay provides a tool to investigate the pharmacology of GGTase-I inhibitors.

scholarly journals Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 903
Author(s):  
Xiao-Mei Zhang ◽  
De-Gao Chen ◽  
Shengwen Calvin Li ◽  
Bo Zhu ◽  
Zhong-Jun Li
Keyword(s):  
Metabolic Regulation ◽  
Transcriptional Profiling ◽  
Tumor Development ◽  
Metabolic Reprogramming ◽  
Cancer Therapies ◽  
Functional Heterogeneity ◽  
Tumor Associated Macrophages ◽  
Metabolic Remodeling ◽  
And Function ◽  
Mapping Models

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous “camouflage” in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages’ ontogeny in macrophages’ functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs’ origins may help understand the classification of TAMs’ population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.

scholarly journals The Hippo Pathway: A Master Regulatory Network Important in Cancer

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1416
Author(s):  
Qiuping Liu ◽  
Xiaomeng Liu ◽  
Guanbin Song
Keyword(s):  
Metabolic Regulation ◽  
Human Cancer ◽  
Hippo Pathway ◽  
Tumor Development ◽  
Biological Significance ◽  
Cancer Development ◽  
Hippo Signaling ◽  
Complex Regulation ◽  
And Function ◽  
The Hippo Pathway

The Hippo pathway is pervasively activated and has been well recognized to play critical roles in human cancer. The deregulation of Hippo signaling involved in cancer development, progression, and resistance to cancer treatment have been confirmed in several human cancers. Its biological significance and deregulation in cancer have drawn increasing interest in the past few years. A fundamental understanding of the complexity of the Hippo pathway in cancer is crucial for improving future clinical interventions and therapy for cancers. In this review, we try to clarify the complex regulation and function of the Hippo signaling network in cancer development, including its role in signal transduction, metabolic regulation, and tumor development, as well as tumor therapies targeting the Hippo pathway.

scholarly journals Subcutaneous neurotrophin-3 infusion induces corticospinal neuroplasticity and improvements in dexterity and walking in elderly rats after large cortical strokes

2018 ◽  
Author(s):  
Denise Duricki ◽  
Sotiris Kakanos ◽  
Barbara Haenzi ◽  
Wayman Christina ◽  
Diana Cash ◽  
...  
Keyword(s):  
Muscle Spindles ◽  
Time Frame ◽  
Sensory Function ◽  
Subcutaneous Infusion ◽  
Delayed Treatment ◽  
Neurotrophin 3 ◽  
Cortical Stroke ◽  
High Doses ◽  
And Function ◽  
Sensorimotor Recovery

AbstractThere is an urgent need for a therapy which reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. Neurotrophin-3 (NT3) is a growth factor made by muscle spindles and skin which is required for the survival, development and function of locomotor circuits involving afferents from muscle and skin that mediate proprioception and tactile sensation. We set out to determine whether subcutaneous supplementation of NT3 improves sensorimotor recovery after stroke in elderly rats. We show that one-month-long subcutaneous infusion of NT3 protein induces sensorimotor recovery after cortical stroke in elderly rats. Specifically, in a randomised, blinded pre-clinical trial, we show improved dexterity, walking and sensory function in rats following cortical ischemic stroke when treatment with NT3 is initiated 24 hours after stroke. Importantly, NT-3 was given in a clinically-feasible timeframe via this straightforward route. MRI and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, anterograde tracing showed that corticospinal axons from the less-affected hemisphere sprouted in the spinal cord from cervical levels 2 to 8. Importantly, Phase I and II clinical trials by others show that repeated, subcutaneously administered high doses of recombinant NT-3 are safe and well tolerated in humans with other conditions. This paves the way for NT-3 as a therapy for stroke.

trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues

Development ◽  
1993 ◽  
Vol 118 (2) ◽  
pp. 463-475 ◽  
Author(s):  
L. Tessarollo ◽  
P. Tsoulfas ◽  
D. Martin-Zanca ◽  
D.J. Gilbert ◽  
N.A. Jenkins ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
Expression Patterns ◽  
Developmental Expression ◽  
Receptor System ◽  
Nerve Growth ◽  
Trk Receptor ◽  
Neurotrophin 3 ◽  
Neuronal Tissues

The Trk family of tyrosine kinases encodes receptors for nerve growth factor-related neurotrophins. Here we present a developmental expression study of trkC, which encodes a receptor for neurotrophin-3 (NT-3). Like the related genes, trk and trkB, trkC is expressed primarily in neural lineages although the pattern is complex and includes non-neuronal cells. Direct comparison with trk and trkB developmental expression patterns permits the following observations. (1) trkC is expressed in novel neural tissues where other Trk genes are silent. (2) Some tissues appear to coexpress trkB and trkC receptors in the embryo and in the adult. (3) trkC expression can be detected in the gastrulating embryo. These data provide insights into the role of Trk-family receptors and nerve growth factor-related neurotrophins during development and suggest that, in addition to regulating neuronal survival and differentiation, the neurotrophin/Trk receptor system may have broader physiological effects. Finally, interspecific mouse backcrosses have been used to map the location of each of the Trk genes on mouse chromosomes. Alignment with available chromosomal maps identify possible linkage between the Trk genes and known neurological mutations.

The hSkn-1a POU transcription factor enhances epidermal stratification by promoting keratinocyte proliferation

2001 ◽  
Vol 114 (10) ◽  
pp. 1913-1923 ◽  
Author(s):  
J. Hildesheim ◽  
U. Kuhn ◽  
C.L. Yee ◽  
R.A. Foster ◽  
K.B. Yancey ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Human Keratinocytes ◽  
Dominant Negative ◽  
Keratinocyte Differentiation ◽  
Transactivation Domain ◽  
Hacat Keratinocytes ◽  
Primary Human Keratinocytes ◽  
Keratinocyte Proliferation ◽  
Proliferation And Differentiation ◽  
Epidermal Homeostasis

Skn-1a is a POU transcription factor that is primarily expressed in the epidermis and is known to modulate the expression of several genes associated with keratinocyte differentiation. However, the formation of a stratified epidermis requires a carefully controlled balance between keratinocyte proliferation and differentiation, and a role for Skn-1a in this process has not been previously demonstrated. Here, our results show, surprisingly, that human Skn-1a contributes to epidermal stratification by primarily promoting keratinocyte proliferation and secondarily by enhancing the subsequent keratinocyte differentiation. In organotypic raft cultures of both primary human keratinocytes and immortalized HaCaT keratinocytes, human Skn-1a expression is associated with increased keratinocyte proliferation and re-epithelialization of the dermal substrates, resulting in increased numbers of keratinocytes available for the differentiation process. In these same raft cultures, human Skn-1a expression enhances the phenotypic changes of keratinocyte differentiation and the upregulated expression of keratinocyte differentiation genes. Conversely, expression of a dominant negative human Skn-1a transcription factor lacking the C-terminal transactivation domain blocks keratinocytes from proliferating and stratifying. Keratinocyte stratification is dependent on a precise balance between keratinocyte proliferation and differentiation, and our results suggest that human Skn-1a has an important role in maintaining epidermal homeostasis by promoting keratinocyte proliferation.

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