Smad4/DPC4

McCarthy, Andréa; Chetty, Runjan

doi:10.1136/jclinpath-2018-205095

Cited by 54 publications

(46 citation statements)

References 46 publications

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“…However, in advanced tumors with high expression, TGF-β stimulates carcinogenesis and metastasis[12-14]. Furthermore, increased TGF-β expression inactivates the tumor suppressor gene Smad4/DPC4, the loss of which is commonly implicated in PC tumor progression[15,16]. TGF-β is also considered to be a negative regulator of skeletal muscle via the Smad2/3 pathway, which contributes to myopenia via myostatin, activin and inhibin signaling[17].…”

Section: Pancreatic Cancer Induced Cachexiamentioning

confidence: 99%

Molecular therapeutic strategies targeting pancreatic cancer induced cachexia

Yakovenko

Cameron

Treviño

2018

WJGS

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Pancreatic cancer (PC) induced cachexia is a complex metabolic syndrome associated with significantly increased morbidity and mortality and reduced quality of life. The pathophysiology of cachexia is complex and poorly understood. Many molecular signaling pathways are involved in PC and cachexia. Though our understanding of cancer cachexia is growing, therapeutic options remain limited. Thus, further discovery and investigation of the molecular signaling pathways involved in the pathophysiology of cachexia can be applied to development of targeted therapies. This review focuses on three main pathophysiologic processes implicated in the development and progression of cachexia in PC, as well as their utility in the discovery of novel targeted therapies.Skeletal muscle wasting is the most prominent pathophysiologic anomaly in cachectic patients and driven by multiple regulatory pathways. Several known molecular pathways that mediate muscle wasting and cachexia include transforming growth factor-beta (TGF-β), myostatin and activin, IGF-1/PI3K/AKT, and JAK-STAT signaling. TGF-β antagonism in cachectic mice reduces skeletal muscle catabolism and weight loss, while improving overall survival. Myostatin/activin inhibition has a great therapeutic potential since it plays an essential role in skeletal muscle regulation. Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) leads to increased ubiquitination associated proteolysis, inhibition of myogenesis, and decreased muscle mass in PC induced cachexia. IGFBP-3 antagonism alleviates muscle cell wasting.Another component of cachexia is profound systemic inflammation driven by pro-cachectic cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon gamma (INF-γ). IL-6 antagonism has been shown to reduce inflammation, reduce skeletal muscle loss, and ameliorate cachexia. While TNF-α inhibitors are clinically available, blocking TNF-α signaling is not effective in the treatment of cancer cachexia. Blocking the synthesis or action of acute phase reactants and cytokines is a feasible therapeutic strategy, but no anti-cytokine therapies are currently approved for use in PC. Metabolic alterations such as increased energy expenditure and gluconeogenesis, insulin resistance, fat tissue browning, excessive oxidative stress, and proteolysis with amino acid mobilization support tumor growth and the development of cachexia. Current innovative nutritional strategies for cachexia management include ketogenic diet, utilization of natural compounds such as silibinin, and supplementation with ω3-polyunsaturated fatty acids. Elevated ketone bodies exhibit an anticancer and anticachectic effect. Silibinin has been shown to inhibit growth of PC cells, induce metabolic alterations, and reduce myofiber degradation. Consumption of ω3-polyunsaturated fatty acids has been shown to significantly decrease resting energy expenditure and regulate metabolic dysfunction.

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Section: Pancreatic Cancer Induced Cachexiamentioning

confidence: 99%

Molecular therapeutic strategies targeting pancreatic cancer induced cachexia

Yakovenko

Cameron

Treviño

2018

WJGS

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“…Studies have found that Smad4 is closely related to cell proliferation and apoptosis (15)(16)(17). It has been found in tumor research that Smad4 is a tumor suppressor gene, and its decreased or absent expression in a variety of tumors has been found to lead to the abnormal proliferation of tissues and cells (19,20); however, it has been found in some studies of cardiovascular diseases that TGF-β1/Smad4 can inhibit cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…In the classical TGF-β pathway, activated Smad2/3 and Smad4 form the SMAD complex, which translocates to the nucleus (14). Smad4 is considered to be a tumor suppressor gene that is closely related to cell apoptosis (15)(16)(17). Imbalance of Smad4 expression in the TGF-β signaling pathway may lead to various diseases, including cancers, fibrous lesions, metabolic diseases and cardiovascular diseases (18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Effects of Smad4 on the expression of caspase‑3 and Bcl‑2 in human gingival fibroblasts cultured on 3D PLGA scaffolds induced by compressive force

Zhao

Wang

et al. 2021

Int J Mol Med

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Human gingival fibroblasts (HGFs) are the main cells that comprise gingival tissue, where they transfer mechanical signals under physiological and pathological conditions. The exact mechanism underlying gingival tissue reconstruction under compressive forces remains unclear. The present study aimed to explore the effects of Smad4, caspase-3 and Bcl-2 on the proliferation of HGFs induced by compressive force. HGFs were cultured on poly(lactide-co-glycolide) (PLGA) scaffolds under an optimal compressive force of 25 g/cm 2 . Cell viability was determined via Cell Counting Kit-8 assays at 0, 12, 24, 48 and 72 h. The expression levels of Smad4, caspase-3 and Bcl-2 were measured via reverse transcription-quantitative PCR and western blotting. The application of compressive force on HGFs for 24 h resulted in a significant increase in cell proliferation and Bcl-2 expression, but a significant decrease in the expression of Smad4 and caspase-3; however, inverse trends were observed by 72 h. Subsequently, a lentivirus was used to overexpress Smad4 in HGFs, which attenuated the effects of compressive force on HGF proliferation and Bcl-2 expression, but enhanced caspase-3 expression, suggesting that Smad4 may regulate compressive force-induced apoptosis in HGFs. In conclusion, these findings increased understanding regarding the mechanisms of compressive force-induced HGF proliferation and apoptosis, which may provide further insight for improving the efficacy and stability of orthodontic treatment.

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“…TSPO and SMAD4 play an important role in steroid synthesis [ 1 , 3 ], but the current research on these two genes mainly focuses on mitochondrial function [ 14 ], oxidative stress [ 15 ] and signal transduction [ 16 ]. Several studies reported that TSPO ligand promoted pregnenolone synthesis [ 14 ], and TGF-β/SMAD4 signaling pathway regulated steroid production and ovarian development [ 17 ], but these studies are rare in fish.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization and Functional Analysis of Two Steroidogenic Genes TSPO and SMAD4 in Yellow Catfish

Chen

Zhong

Song

et al. 2021

IJMS

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The steroid hormones are required for gonadal development in fish. The present study was undertaken to characterize the cDNA and promoter sequences of TSPO and SMAD4 genes in yellow catfish Pelteobagrus fulvidraco, explored the mRNA tissue expression and deciphered their promoter regions. Yellow catfish TSPO and SMAD4 shared the similar domains to the corresponding genes from other vertebrates. The TSPO and SMAD4 mRNAs were widely expressed in the detected tissues, but at different levels. Several transcription factors were predicted, such as Sp, GATA, AP1, SOX1, SRY, STAT, HNF4α, PPARγ, Pu.1 and FOXL2. PPARγ overexpression increased but STAT3 overexpression reduced TSPO promoter activity, and FOXL2 overexpression inhibited the promoter activity of TSPO and SMAD4. The site mutation and EMSA analysis indicated that TSPO promoter possessed STAT3 and FOXL2 sites. Overall, our provided the novel understanding into the transcriptionally regulatory mechanisms of TSPO and SMAD4 in fish.

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Smad4/DPC4

Cited by 54 publications

References 46 publications

Molecular therapeutic strategies targeting pancreatic cancer induced cachexia

Molecular therapeutic strategies targeting pancreatic cancer induced cachexia

Effects of Smad4 on the expression of caspase‑3 and Bcl‑2 in human gingival fibroblasts cultured on 3D PLGA scaffolds induced by compressive force

Molecular Characterization and Functional Analysis of Two Steroidogenic Genes TSPO and SMAD4 in Yellow Catfish

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