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Biomolecules Oct 2022The insulin family consists of insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor 2 (IGF-2), their receptors (IR, IGF-1R and IGF-2R), and their... (Review)
Review
The insulin family consists of insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor 2 (IGF-2), their receptors (IR, IGF-1R and IGF-2R), and their binding proteins. All three ligands are involved in cell proliferation, apoptosis, protein synthesis and metabolism due to their homologous sequences and structural similarities. Insulin-like growth factor 2, a member of the insulin family, plays an important role in embryonic development, metabolic disorders, and tumorigenesis by combining with three receptors with different degrees of affinity. The main pathological feature of various fibrotic diseases is the excessive deposition of extracellular matrix (ECM) after tissue and organ damage, which eventually results in organic dysfunction because scar formation replaces tissue parenchyma. As a mitogenic factor, IGF-2 is overexpressed in many fibrotic diseases. It can promote the proliferation of fibroblasts significantly, as well as the production of ECM in a time- and dose-dependent manner. This review aims to describe the expression changes and fibrosis-promoting effects of IGF-2 in the skin, oral cavity, heart, lung, liver, and kidney fibrotic tissues.
Topics: Humans; Insulin-Like Growth Factor II; Receptor, Insulin; Fibrosis; Extracellular Matrix; Insulin
PubMed: 36358907
DOI: 10.3390/biom12111557 -
Nature Communications Sep 2022Chronic activation of stress hormones such as glucocorticoids leads to skeletal muscle wasting in mammals. However, the molecular events that mediate...
Chronic activation of stress hormones such as glucocorticoids leads to skeletal muscle wasting in mammals. However, the molecular events that mediate glucocorticoid-induced muscle wasting are not well understood. Here, we show that SIRT6, a chromatin-associated deacetylase indirectly regulates glucocorticoid-induced muscle wasting by modulating IGF/PI3K/AKT signaling. Our results show that SIRT6 levels are increased during glucocorticoid-induced reduction of myotube size and during skeletal muscle atrophy in mice. Notably, overexpression of SIRT6 spontaneously decreases the size of primary myotubes in a cell-autonomous manner. On the other hand, SIRT6 depletion increases the diameter of myotubes and protects them against glucocorticoid-induced reduction in myotube size, which is associated with enhanced protein synthesis and repression of atrogenes. In line with this, we find that muscle-specific SIRT6 deficient mice are resistant to glucocorticoid-induced muscle wasting. Mechanistically, we find that SIRT6 deficiency hyperactivates IGF/PI3K/AKT signaling through c-Jun transcription factor-mediated increase in IGF2 expression. The increased activation, in turn, leads to nuclear exclusion and transcriptional repression of the FoxO transcription factor, a key activator of muscle atrophy. Further, we find that pharmacological inhibition of SIRT6 protects against glucocorticoid-induced muscle wasting in mice by regulating IGF/PI3K/AKT signaling implicating the role of SIRT6 in glucocorticoid-induced muscle atrophy.
Topics: Animals; Chromatin; Glucocorticoids; Mammals; Mice; Muscle Fibers, Skeletal; Muscular Atrophy; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sirtuins; Somatomedins; Transcription Factors
PubMed: 36109503
DOI: 10.1038/s41467-022-32905-w -
Science Advances Jul 2023The progression of noninvasive ductal carcinoma in situ to invasive ductal carcinoma for patients with breast cancer results in a significantly poorer prognosis and is...
The progression of noninvasive ductal carcinoma in situ to invasive ductal carcinoma for patients with breast cancer results in a significantly poorer prognosis and is the precursor to metastatic disease. In this work, we have identified insulin-like growth factor-binding protein 2 (IGFBP2) as a potent adipocrine factor secreted by healthy breast adipocytes that acts as a barrier against invasive progression. In line with this role, adipocytes differentiated from patient-derived stromal cells were found to secrete IGFBP2, which significantly inhibited breast cancer invasion. This occurred through binding and sequestration of cancer-derived IGF-II. Moreover, depletion of IGF-II in invading cancer cells using small interfering RNAs or an IGF-II-neutralizing antibody ablated breast cancer invasion, highlighting the importance of IGF-II autocrine signaling for breast cancer invasive progression. Given the abundance of adipocytes in the healthy breast, this work exposes the important role they play in suppressing cancer progression and may help expound upon the link between increased mammary density and poorer prognosis.
Topics: Female; Humans; Adipocytes; Antibodies, Neutralizing; Breast; Breast Neoplasms; Insulin-Like Growth Factor II
PubMed: 37436978
DOI: 10.1126/sciadv.adg1840 -
Reviews in Endocrine & Metabolic... Mar 2021Growth hormone (GH) actions impact growth, metabolism, and body composition and have been associated with aging and longevity. Lack of GH results in slower growth,... (Review)
Review
Growth hormone (GH) actions impact growth, metabolism, and body composition and have been associated with aging and longevity. Lack of GH results in slower growth, delayed maturation, and reduced body size and can lead to delayed aging, increased healthspan, and a remarkable extension of longevity. Adult body size, which is a GH-dependent trait, has a negative association with longevity in several mammalian species. Mechanistic links between GH and aging include evolutionarily conserved insulin/insulin-like growth factors and mechanistic target of rapamycin signaling pathways in accordance with long-suspected trade-offs between anabolic/growth processes and longevity. Height and the rate and regulation of GH secretion have been related to human aging, but longevity is not extended in humans with syndromes of GH deficiency or resistance. However, the risk of age-related chronic disease is reduced in individuals affected by these syndromes and various indices of increased healthspan have been reported.
Topics: Aging; Animals; Growth Hormone; Humans; Insulin-Like Growth Factor I; Longevity; Signal Transduction
PubMed: 33001358
DOI: 10.1007/s11154-020-09593-2 -
The Journal of Pathology Feb 2023Colorectal cancer (CRC) is one of the most common cancers worldwide. The tumor microenvironment exerts crucial effects in driving CRC progression. Cancer-associated...
Colorectal cancer (CRC) is one of the most common cancers worldwide. The tumor microenvironment exerts crucial effects in driving CRC progression. Cancer-associated fibroblasts (CAFs) serve as one of the most important tumor microenvironment components promoting CRC progression. This study aimed to elucidate the novel molecular mechanisms of CAF-secreted insulin-like growth factor (IGF) 2 in colorectal carcinogenesis. Our results indicated that IGF2 was a prominent factor upregulated in CAFs compared with normal fibroblasts. CAF-derived conditioned media (CM) promoted tumor growth, migration, and invasion of HCT 116 and DLD-1 cells. IGF1R expression is significantly increased in CRC, serving as a potent receptor in response to IGF2 stimulation and predicting unfavorable outcomes for CRC patients. Apart from the PI3K-AKT pathway, RNA-seq analysis revealed that the YAP1-target signature serves as a prominent downstream effector to mediate the oncogenic signaling of IGF2-IGF1R. By single-cell RNA sequencing (scRNA-seq) and immunohistochemical validation, IGF2 was found to be predominantly secreted by CAFs, whereas IGF1R was expressed mainly by cancer cells. IGF2 triggers the nuclear accumulation of YAP1 and upregulates YAP1 target signatures; however, these effects were abolished by either IGF1R knockdown or inhibition with picropodophyllin (PPP), an IGF1R inhibitor. Using CRC organoid and in vivo studies, we found that cotargeting IGF1R and YAP1 with PPP and verteporfin (VP), a YAP1 inhibitor, enhanced antitumor effects compared with PPP treatment alone. In conclusion, this study revealed a novel molecular mechanism by which CAFs promote CRC progression. The findings highlight the translational potential of the IGF2-IGF1R-YAP1 axis as a prognostic biomarker and therapeutic target for CRC. © 2022 The Pathological Society of Great Britain and Ireland.
Topics: Humans; Cancer-Associated Fibroblasts; Phosphatidylinositol 3-Kinases; Cell Line, Tumor; Signal Transduction; Carcinogenesis; Colorectal Neoplasms; Cell Proliferation; Tumor Microenvironment; Insulin-Like Growth Factor II; Receptor, IGF Type 1
PubMed: 36373776
DOI: 10.1002/path.6033 -
Aging Aug 2022
Topics: Growth Hormone; Insulin-Like Growth Factor I
PubMed: 36063137
DOI: 10.18632/aging.204257 -
Cells Jan 2022Over the past two decades, interest in the role of the somatotroph growth hormone/insulin-like growth factor (GH/IGF1) axis in multiple aspects of physiology and...
Over the past two decades, interest in the role of the somatotroph growth hormone/insulin-like growth factor (GH/IGF1) axis in multiple aspects of physiology and pathology has grown exponentially [...].
Topics: Aging; Animals; Genomics; Growth Hormone; Humans; Signal Transduction; Somatomedins
PubMed: 35053333
DOI: 10.3390/cells11020217 -
Biological Reviews of the Cambridge... Jun 2020The nervous system communicates with peripheral tissues through nerve fibres and the systemic release of hypothalamic and pituitary neurohormones. Communication between... (Review)
Review
The nervous system communicates with peripheral tissues through nerve fibres and the systemic release of hypothalamic and pituitary neurohormones. Communication between the nervous system and the largest human organ, skin, has traditionally received little attention. In particular, the neuro-regulation of sebaceous glands (SGs), a major skin appendage, is rarely considered. Yet, it is clear that the SG is under stringent pituitary control, and forms a fascinating, clinically relevant peripheral target organ in which to study the neuroendocrine and neural regulation of epithelia. Sebum, the major secretory product of the SG, is composed of a complex mixture of lipids resulting from the holocrine secretion of specialised epithelial cells (sebocytes). It is indicative of a role of the neuroendocrine system in SG function that excess circulating levels of growth hormone, thyroxine or prolactin result in increased sebum production (seborrhoea). Conversely, growth hormone deficiency, hypothyroidism, and adrenal insufficiency result in reduced sebum production and dry skin. Furthermore, the androgen sensitivity of SGs appears to be under neuroendocrine control, as hypophysectomy (removal of the pituitary) renders SGs largely insensitive to stimulation by testosterone, which is crucial for maintaining SG homeostasis. However, several neurohormones, such as adrenocorticotropic hormone and α-melanocyte-stimulating hormone, can stimulate sebum production independently of either the testes or the adrenal glands, further underscoring the importance of neuroendocrine control in SG biology. Moreover, sebocytes synthesise several neurohormones and express their receptors, suggestive of the presence of neuro-autocrine mechanisms of sebocyte modulation. Aside from the neuroendocrine system, it is conceivable that secretion of neuropeptides and neurotransmitters from cutaneous nerve endings may also act on sebocytes or their progenitors, given that the skin is richly innervated. However, to date, the neural controls of SG development and function remain poorly investigated and incompletely understood. Botulinum toxin-mediated or facial paresis-associated reduction of human sebum secretion suggests that cutaneous nerve-derived substances modulate lipid and inflammatory cytokine synthesis by sebocytes, possibly implicating the nervous system in acne pathogenesis. Additionally, evidence suggests that cutaneous denervation in mice alters the expression of key regulators of SG homeostasis. In this review, we examine the current evidence regarding neuroendocrine and neurobiological regulation of human SG function in physiology and pathology. We further call attention to this line of research as an instructive model for probing and therapeutically manipulating the mechanistic links between the nervous system and mammalian skin.
Topics: Animals; Brain; Dopamine; Growth Hormone; Humans; Hypothalamo-Hypophyseal System; Neurosecretory Systems; Peripheral Nervous System; Prolactin; Sebaceous Glands; Sebum; Skin; Skin Physiological Phenomena; Somatomedins; Stem Cells; Thyroid Gland
PubMed: 31970855
DOI: 10.1111/brv.12579 -
Diabetes Jun 2023
Topics: Hexosaminidase A; Liver; Somatomedins; Muscle, Skeletal; Glucose
PubMed: 37205863
DOI: 10.2337/dbi22-0040 -
Cold Spring Harbor Perspectives in... Mar 2020Within the realm of zoological study, the question of how an organism reaches a specific size has been largely unexplored. Recently, studies performed to understand the... (Review)
Review
Within the realm of zoological study, the question of how an organism reaches a specific size has been largely unexplored. Recently, studies performed to understand the regulation of organ size have revealed that both cellular signals and external cues contribute toward the determination of total cell mass within each organ. The establishment of final organ size requires the precise coordination of cell growth, proliferation, and survival throughout development and postnatal life. In the mammalian heart, the regulation of size is biphasic. During development, cardiomyocyte proliferation predominantly determines cardiac growth, whereas in the adult heart, total cell mass is governed by signals that regulate cardiac hypertrophy. Here, we review the current state of knowledge regarding the extrinsic factors and intrinsic mechanisms that control heart size during development. We also discuss the metabolic switch that occurs in the heart after birth and precedes homeostatic control of postnatal heart size.
Topics: Animals; Cardiomegaly; Cell Cycle; Cell Proliferation; Cell Survival; Heart; Humans; Hypertrophy; Myocardium; Myocytes, Cardiac; Organ Size; Organogenesis; Signal Transduction; Somatomedins; Zoology
PubMed: 31615785
DOI: 10.1101/cshperspect.a037150