Yu Ping Feng San Exert Anti-Angiogenesis Effects through the Inhibition of TSLP-STAT3 Signaling Pathways in Hepatocellular Carcinoma

Background. Clinically, Yu ping feng san (YPFS) has been extensively used as a medication for treating immune deficiency, and YPFS is combined with chemotherapy drugs to treat cancer, including hepatocellular carcinoma (HCC), lung cancer, and pancreatic cancer. Previous research has shown that YPFS has a therapeutic effect on HCC by improving the immunosuppressive state of the liver cancer microenvironment. The present study aimed to investigate the effect of YPFS on angiogenesis of HCC. Methods. High-performance liquid chromatography (HPLC) was used to certify the composition of YPFS. An orthotopic transplanted model of murine HCC was entrenched. Immunohistochemistry was used to observe the changes of the microvessel density (MVD). The MTT assay was used to detect the cell viability. ELISA was performed to analyze the expression of related factors. Western blot was used to analyze the protein expression. Tube formation assay was used to analyze the anti-angiogenic efficiency. Results. YPFS significantly reduced the tumor volume and weight, thus exerted the growth inhibitory effect. The level of MVD and VEGF was obviously decreased in YPFS-treated HCC-bearing mice, and the YPFS treatment also reduced the VEGF level in Hepa1-6 cells. Further study revealed that the expression of TSLP/TSLPR and p-STAT3/STAT3 was decreased by YPFS. The level of MVD and VEGF and the expression of TSLP/TSLPR and p-STAT3/STAT3 in tumor tissue and Hepa1-6 cells were suppressed by incubation with the anti-TSLP antibody, whereas treatment with the anti-TSLP antibody in YPFS-treated cells did not cause further significant inhibition compared with the cells treated only with YPFS. More importantly, YPFS inhibited proliferation, expression of p-STAT3/STAT3, and tube formation of HUVECs induced by TSLP. Conclusions. These results indicated that YPFS attenuated the activation of the TSLP-STAT3 signaling pathway by inhibiting the immune-related factor-TSLP, thereby inhibiting the formation of hepatic microvessels and exerting an anti-HCC effect.

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CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01769-7 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Zhongwei Zhao ◽

Jingjing Song ◽

Bufu Tang ◽

Shiji Fang ◽

Dengke Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Migration ◽

Real Time ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Signaling Axis

Abstract Background Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. Methods The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. Results In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. Conclusion The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.

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3-Formylchromone Counteracts STAT3 Signaling Pathway by Elevating SHP-2 Expression in Hepatocellular Carcinoma

Biology ◽

10.3390/biology11010029 ◽

2021 ◽

Vol 11 (1) ◽

pp. 29

Author(s):

Chakrabhavi Dhananjaya Mohan ◽

Min Hee Yang ◽

Shobith Rangappa ◽

Arunachalam Chinnathambi ◽

Sulaiman Ali Alharbi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Tyrosine Kinases ◽

Present Report ◽

Migration And Invasion ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Substantial Toxicity ◽

Transcription 3 ◽

Constitutive Phosphorylation

Hepatocellular carcinoma (HCC) is one of the leading cancers that contribute to a large number of deaths throughout the globe. The signal transducer and activator of transcription 3 (STAT3) is a tumorigenic protein that is overactivated in several human malignancies including HCC. In the present report, the effect of 3-formylchromone (3FC) on the STAT3 signaling pathway in the HCC model was investigated. 3FC downregulated the constitutive phosphorylation of STAT3 and non-receptor tyrosine kinases such as JAK1 and JAK2. It also suppressed the transportation of STAT3 to the nucleus and reduced its DNA-binding ability. Pervanadate treatment overrode the 3FC-triggered STAT3 inhibition, and the profiling of cellular phosphatase expression revealed an increase in SHP-2 levels upon 3FC treatment. The siRNA-driven deletion of SHP-2 led to reinstate STAT3 activation. 3FC downmodulated the levels of various oncogenic proteins and decreased CXCL12-driven cell migration and invasion. Interestingly, 3FC did not exhibit any substantial toxicity, whereas it significantly regressed tumor growth in an orthotopic HCC mouse model and abrogated lung metastasis. Overall, 3FC can function as a potent agent that can display antitumor activity by targeting STAT3 signaling in HCC models.

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Physagulide Q suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells by regulating the ROS-JAK2/Src-STAT3 signaling pathway

RSC Advances ◽

10.1039/c6ra25032g ◽

2017 ◽

Vol 7 (21) ◽

pp. 12793-12804 ◽

Cited By ~ 4

Author(s):

Yan-Wei Yang ◽

Lei Yang ◽

Chao Zhang ◽

Cai-Yun Gao ◽

Ting Ma ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Natural Compound ◽

Carcinoma Cells ◽

Human Hepatocellular Carcinoma ◽

Hepatocellular Carcinoma Cells ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Physalis Angulata ◽

Human Hepatocellular Carcinoma Cells

Physagulide Q (PQ), a new natural compound, was isolated from Physalis angulata L. in our laboratory.

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Peri-tumor fibroblasts promote tumorigenesis and metastasis of hepatocellular carcinoma via Interleukin6/STAT3 signaling pathway

Cancer Management and Research ◽

10.2147/cmar.s192263 ◽

2019 ◽

Vol Volume 11 ◽

pp. 2889-2901 ◽

Cited By ~ 4

Author(s):

Zhenxiong Zhao ◽

Si Xiong ◽

Ronghua Wang ◽

Yawen Li ◽

Xiju Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

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Pyrimidine-2,4-dione Targets STAT3 Signaling Pathway to Induce Cytotoxicity in Hepatocellular Carcinoma Cells

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2021.128332 ◽

2021 ◽

pp. 128332

Author(s):

Ayyiliath M Sajith ◽

Kereyagalahally H. Narasimhamurthy ◽

Muthu K. Shanmugam ◽

Shobith Rangappa ◽

S. Chandra Nayak ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Carcinoma Cells ◽

Hepatocellular Carcinoma Cells ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

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Longer warm ischemia can accelerate tumor growth through the induction of HIF-1α and the IL-6-JAK-STAT3 signaling pathway in a rat hepatocellular carcinoma model

Journal of Hepato-Biliary-Pancreatic Sciences ◽

10.1002/jhbp.406 ◽

2016 ◽

Vol 23 (12) ◽

pp. 771-779 ◽

Cited By ~ 5

Author(s):

Yuhei Hamaguchi ◽

Akira Mori ◽

Yasuhiro Fujimoto ◽

Takashi Ito ◽

Taku Iida ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Growth ◽

Signaling Pathway ◽

Warm Ischemia ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

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Tris(dibenzylideneacetone)dipalladium(0) (Tris DBA) Abrogates Tumor Progression in Hepatocellular Carcinoma and Multiple Myeloma Preclinical Models by Regulating the STAT3 Signaling Pathway

Cancers ◽

10.3390/cancers13215479 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5479

Author(s):

Loukik Arora ◽

Chakrabhavi Dhananjaya Mohan ◽

Min Hee Yang ◽

Shobith Rangappa ◽

Amudha Deivasigamani ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Multiple Myeloma ◽

Nuclear Translocation ◽

Binding Ability ◽

Stat3 Signaling ◽

Expression Of Genes ◽

Stat3 Signaling Pathway ◽

Significant Toxicity ◽

Tumor Tissues ◽

Oncogenic Transcription Factor

STAT3 is an oncogenic transcription factor that controls the expression of genes associated with oncogenesis and malignant progression. Persistent activation of STAT3 is observed in human malignancies, including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Here, we have investigated the action of Tris(dibenzylideneacetone) dipalladium 0 (Tris DBA) on STAT3 signaling in HCC and MM cells. Tris DBA decreased cell viability, increased apoptosis, and inhibited IL-6 induced/constitutive activation of STAT3, JAK1, JAK2, and Src in HCC and MM cells. Tris DBA downmodulated the nuclear translocation of STAT3 and reduced its DNA binding ability. It upregulated the expression of SHP2 (protein and mRNA) to induce STAT3 dephosphorylation, and the inhibition of SHP2 reversed this effect. Tris DBA downregulated the expression of STAT3-driven genes, suppressed cell migration/invasion. Tris DBA significantly inhibited tumor growth in xenograft MM and orthotopic HCC preclinical mice models with a reduction in the expression of various prosurvival biomarkers in MM tumor tissues without displaying significant toxicity. Overall, Tris DBA functions as a good inhibitor of STAT3 signaling in preclinical HCC and MM models.

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Erratum for: Long Noncoding RNA HOST2 Promotes Epithelial- Mesenchymal Transition, Proliferation, Invasion and Migration of Hepatocellular Carcinoma Cells by Activating the JAK2-STAT3 Signaling Pathway

Cellular Physiology and Biochemistry ◽

10.33594/000000259 ◽

2020 ◽

Vol 54 (4) ◽

pp. 797-797

Keyword(s):

Hepatocellular Carcinoma ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cells ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

And Migration

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Tofacitinib Ameliorates Lipopolysaccharide-Induced Acute Kidney Injury by Blocking the JAK-STAT1/STAT3 Signaling Pathway

BioMed Research International ◽

10.1155/2021/8877056 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Yang Yun ◽

Jingyu Chen ◽

Xuejiao Wang ◽

Yingzhuo Li ◽

Zhifan Hu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Inhibitory Effect ◽

Janus Kinase ◽

Protective Effects ◽

Lps Challenge ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Septic Acute Kidney Injury ◽

Underlying Mechanisms

Septic acute kidney injury (AKI) is the most common AKI syndrome in the intensive care unit (ICU), and it accounts for approximately half of AKI cases. Tofacitinib (TOFA) is a pan-Janus kinase (JAK) inhibitor that exhibits potent anti-inflammatory activity in rheumatoid arthritis. However, no study has examined the functional role of TOFA in septic AKI. In the present study, we investigated the protective effects of TOFA on septic AKI and the underlying mechanisms. A lipopolysaccharide- (LPS-) induced AKI model was established in C57BL/6 mice via an intraperitoneal injection of LPS (10 mg/kg). One hour after LPS challenge, the mice were orally administered TOFA (5, 10, or 15 mg/kg) every 6 h until sacrifice at 24 h. We found that TOFA significantly ameliorated LPS-induced renal histopathological changes and dysfunction. TOFA also suppressed the expression levels of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ) and the parameters of oxidative stress (MDA, GSH, SOD, and CAT) in kidney tissues. These results may be associated with the inhibitory effect of TOFA on the JAK-STAT1/STAT3 pathway, which was significantly activated by LPS challenge. TOFA treatment also inhibited LPS-induced activation of the TLR4/NF-κB pathway. In conclusion, we revealed that TOFA had a protective effect on LPS-induced AKI, and it may be a promising therapeutic agent for septic AKI.

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