MiRNA-16 inhibited oral squamous carcinoma tumor growth in vitro and in vivo via suppressing Wnt/β-catenin signaling pathway

Abstract SASS6 encodes for the Homo sapiens SAS-6 centriolar assembly protein and is important for proper centrosome formation. Although centrosomes are amplified in a wide variety of tumor types, abnormally high SASS6 expression had previously only been identified in colon cancer. Moreover, the role of SASS6 in esophageal squamous cell carcinoma (ESCC) pathogenesis has not yet been elucidated. The aim of this study was to investigate the role and mechanisms of SASS6 in ESCC. In this study, we found that the mRNA and protein levels of SASS6 were increased in human ESCC samples. In addition, SASS6 protein expression was associated with the esophageal cancer stage and negatively affected survival of patients with ESCC. Furthermore, silencing of SASS6 inhibited cell growth and promoted apoptosis of ESCC cells in vitro and inhibited xenograft tumor formation in vivo. A genetic cluster and pathway analysis showed that SASS6 regulated the p53 signaling pathway. Western blot demonstrated that CCND2, GADD45A and EIF4EBP1 protein expression decreased and that TP53 protein expression increased after the knockdown of SASS6 in ESCC cells. Therefore, SASS6 promoted the proliferation of esophageal cancer by inhibiting the p53 signaling pathway. SASS6 has potential as a novel tumor marker and a therapeutic target for ESCC.

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The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90455.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. G1150-G1158 ◽

Cited By ~ 45

Author(s):

Sharon DeMorrow ◽

Heather Francis ◽

Eugenio Gaudio ◽

Julie Venter ◽

Antonio Franchitto ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Growth ◽

Wnt Signaling ◽

Signaling Pathway ◽

Calcium Release ◽

Wnt Signaling Pathway ◽

Xenograft Model ◽

Orphan Receptor

Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a Ca2+-dependent pathway involving protein kinase C, or a Ca2+-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun NH2-terminal kinase (JNK). This pathway is associated with growth-suppressing effects in numerous cell types. We have shown that anandamide decreases cholangiocarcinoma growth in vitro. Therefore, we determined the effects of anandamide on cholangiocarcinoma tumor growth in vivo using a xenograft model and evaluated the effects of anandamide on the noncanonical Wnt signaling pathways. Chronic administration of anandamide decreased tumor growth and was associated with increased Wnt 5a expression in vitro and in vivo. Treatment of cholangiocarcinoma cells with recombinant Wnt 5a decreased cell proliferation in vitro. Neither anandamide nor Wnt 5a affected intracellular calcium release, but both increased the JNK phosphorylation. Stable knockdown of Wnt 5a or Ror2 expression in cholangiocarcinoma cells abolished the effects of anandamide on cell proliferation and JNK activation. Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment. The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.

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MiR-1246 regulates the PI3K/AKT signaling pathway by targeting PIK3AP1 and inhibits thyroid cancer cell proliferation and tumor growth

Molecular and Cellular Biochemistry ◽

10.1007/s11010-021-04290-3 ◽

2021 ◽

Author(s):

Jingyan Li ◽

Zhanlei Zhang ◽

Jieting Hu ◽

Xiaoting Wan ◽

Wei Huang ◽

...

Keyword(s):

Thyroid Cancer ◽

Tumor Growth ◽

Signaling Pathway ◽

Gene Expression Omnibus ◽

Akt Signaling ◽

Akt Phosphorylation ◽

Apoptotic Death ◽

Phosphoinositide 3 Kinase

AbstractOne of the most prevalent forms of endocrine malignancies is thyroid cancer. Herein, we explored the mechanisms whereby miR-1246 is involved in thyroid cancer. Phosphoinositide 3-kinase adapter protein 1 (PIK3AP1) was identified as a potential miR-1246 target, with the online Gene Expression Omnibus (GEO) database. The binding between miR-1246 and PIK3AP1 and the dynamic role of these two molecules in downstream PI3K/AKT signaling were evaluated. Analysis of GEO data demonstrated significant miR-1246 downregulation in thyroid cancer, and we confirmed that overexpression of miR-1246 can inhibit migratory, invasive, and proliferative activity in vitro and tumor growth in vivo. Subsequent studies indicated that miR-1246 overexpression decreased the protein level of PIK3AP1 and the phosphorylation of PI3K and AKT, which were reversed by PIK3AP1 overexpression. At the same time, overexpression of PIK3AP1 also reversed the miR-1246 mimics-induced inhibition proliferative, migratory, and invasive activity, while promoting increases in apoptotic death, confirming that miR-1246 function was negatively correlated with that of PIK3AP1. Subsequently, we found that the miR-1246 mimics-induced inhibition of PI3K/AKT phosphorylation was reversed by the PI3K/AKT activator IGF-1. miR-1246 mimics inhibited proliferative, migratory, and invasive activity while promoting increases in apoptotic death, which were reversed by IGF-1. Furthermore, miR-1246 agomir can inhibit tumor growth in vivo. We confirmed that miR-1246 affects the signaling pathway of PI3K/AKT via targeting PIK3AP1 and inhibits the development of thyroid cancer. Thus, miR-1246 is a new therapeutic target for thyroid cancer.

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Berberine Exerts a Protective Effect on Gut-Vascular Barrier via the Modulation of the Wnt/Beta-Catenin Signaling Pathway During Sepsis

Cellular Physiology and Biochemistry ◽

10.1159/000493412 ◽

2018 ◽

Vol 49 (4) ◽

pp. 1342-1351 ◽

Cited By ~ 8

Author(s):

Yan He ◽

Xiaoming Yuan ◽

Hao Zuo ◽

Ying Sun ◽

Aiwen Feng

Keyword(s):

Protective Effect ◽

Vascular Permeability ◽

Signaling Pathway ◽

Cecal Ligation ◽

Endothelial Permeability ◽

Bacterial Invasion ◽

Beta Catenin ◽

Endotoxin Level

Background/Aims: The gut-vascular barrier (GVB) has recently been depicted to dampen the bacterial invasion of the bloodstream. The intestinal mucosa is a tissue rich in small vessels including capillaries. In this study, the protective effect of berberine on GVB in small bowel mucosa was investigated. Methods: The rat cecal ligation and puncture (CLP) sepsis model was employed to evaluate the effect of berberine on serum endotoxin level and intestinal vascular permeability to Evans blue in vivo. The rat intestinal microvascular endothelial cells (RIMECs) treated by lipopolysaccharide (LPS) were used to assess the effect of berberine on endothelial permeability to FITC-labeled dextran, transendothelial electrical resistance (TEER), and tight junction (TJ) and adherens junction (AJ) expression in vitro. Results: After 24-hr CLP operation the serum endotoxin concentration and gut vascular permeability were significantly increased, while berberine markedly reduced endotoxin level and vascular leakage. In vitro, LPS not only dramatically increased endothelial permeability of RIMECs to FITC-dextran, but also decreased TEER and inhibited claudin-12, beta-catenin and VE-cadherin expression. These effects of LPS were antagonized by berberine. In addition, our in vivo and vitro studies also confirmed that the effect of berberine on GVB could be partially abolished by ICG001. Conclusion: Berberine exerted a protective effect on GVB function in sepsis, which was strictly related to the modulation of the Wnt/beta-catenin signaling pathway.

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[Corrigendum] Ceramide synthase‑4 orchestrates the cell proliferation and tumor growth of liver cancer in vitro and in vivo through the nuclear factor‑κB signaling pathway

Oncology Letters ◽

10.3892/ol.2021.12551 ◽

2021 ◽

Vol 21 (4) ◽

Author(s):

Jinwu Chen ◽

Xiaojie Li ◽

Dengjiao Ma ◽

Tao Liu ◽

Pingping Tian ◽

...

Keyword(s):

Cell Proliferation ◽

Liver Cancer ◽

Tumor Growth ◽

Signaling Pathway ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Ceramide Synthase

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Tumor protein D52 is upregulated in oral squamous carcinoma cells under hypoxia in a hypoxia-inducible-factor-independent manner and is involved in cell death resistance

Cell & Bioscience ◽

10.1186/s13578-021-00634-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yuzo Abe ◽

Yoshiki Mukudai ◽

Mai Kurihara ◽

Asami Houri ◽

Junichiro Chikuda ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Squamous Carcinoma ◽

Cancer Therapeutics ◽

Tumor Xenograft ◽

Independent Manner ◽

Protein Levels ◽

Squamous Carcinoma Cells ◽

Oral Squamous Carcinoma

Abstract Background Tumor protein D52 (TPD52) reportedly plays an important role in the proliferation and metastasis of various cancer cells, including oral squamous cell carcinoma (OSCC) cells, and is expressed strongly at the center of the tumor, where the microenvironment is hypoxic. Thus, the present study investigated the roles of TPD52 in the survival and death of OSCC cells under hypoxia, and the relationship with hypoxia-inducible factor (HIF). We examined the expression of TPD52 in OSCC cells under hypoxic conditions and analyzed the effects of HIF on the modulation of TPD52 expression. Finally, the combinational effects of TPD52 knockdown and HIF inhibition were investigated both in vitro and in vivo. Results The mRNA and protein levels of TPD52 increased in OSCC cells under hypoxia. However, the increase was independent of HIF transcription. Importantly, the observation was due to upregulation of mRNA stability by binding of mRNA to T-cell intercellular antigen (TIA) 1 and TIA-related protein (TIAR). Simultaneous knockdown of TPD52 and inhibition of HIF significantly reduced cell viability. In addition, the in vivo tumor-xenograft experiments showed that TPD52 acts as an autophagy inhibitor caused by a decrease in p62. Conclusions This study showed that the expression of TPD52 increases in OSCC cells under hypoxia in a HIF-independent manner and plays an important role in the proliferation and survival of the cells in concordance with HIF, suggesting that novel cancer therapeutics might be led by TPD52 suppression.

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The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin

10.20944/preprints201903.0045.v1 ◽

2019 ◽

Author(s):

Haneen Amawi ◽

Noor Hussein ◽

Sai HS Boddu ◽

Chandrabose Karthikeyan ◽

Frederick E. Williams ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Biologically Active ◽

Beta Catenin ◽

Lead Compound ◽

Prostate Cancer Cells

Thienopyrimidines are a versatile group of compounds that contain a biologically active pharmacophore and reported to have anticancer efficacy in vitro. Here, we report for the first time, that thieno[3,2-d]pyrimidine - based compounds, designated the RP series, have efficacy in prostate cancer cells. The lead compound, RP-010, was efficacious in PC3 and DU-145 prostate cancer (PC) cells (IC50< 1µM). The cytotoxicity of RP-010 was significantly lower in normal cells. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in the G2 phase of the cell cycle, induced mitotic catastrophe and apoptotic signaling in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) inhibits the wingless-type MMTV (Wnt)/β-catenin signaling pathway, mainly by inducing β-catenin fragmentation, while down regulating important proteins in the pathway, i.e. LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced the nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the signaling pathway. In addition, RP-010 (0.5, 1, 2, and 4 µM) significantly decreased the migration and invasiveness of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations up to 6 µM. In conclusion, RP-10 is a promising anticancer compound in metastatic prostate cancer and did not produce overt toxicity in an in vivo zebrafish model. Future mechanistic and efficacy studies are needed in-vivo to optimize the lead compound RP-010 for clinical use.

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Tumor Protein D52 Is Upregulated in Oral Squamous Carcinoma Cells Under Hypoxia in a Hypoxia-inducible-factor-independent Manner and Is Involved in Cell Death Resistance

10.21203/rs.3.rs-434696/v1 ◽

2021 ◽

Author(s):

Yuzo Abe ◽

Yoshiki Mukudai ◽

Mai Kurihara ◽

Asami Houri ◽

Junichiro Chikuda ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Squamous Carcinoma ◽

Cancer Therapeutics ◽

Tumor Xenograft ◽

Independent Manner ◽

Protein Levels ◽

Squamous Carcinoma Cells ◽

Oral Squamous Carcinoma

Abstract Background. Tumor protein D52 (TPD52) reportedly plays an important role in the proliferation and metastasis of various cancer cells, including oral squamous cell carcinoma (OSCC) cells, and is expressed strongly at the center of the tumor, where the microenvironment is hypoxic. Thus, the present study investigated the roles of TPD52 in the survival and death of OSCC cells under hypoxia, and the relationship with hypoxia-inducible factor (HIF). We examined the expression of TPD52 in OSCC cells under hypoxic conditions and analyzed the effects of HIF on the modulation of TPD52 expression. Finally, the combinational effects of TPD52 knockdown and HIF inhibition were investigated both in vitro and in vivo.Results. The mRNA and protein levels of TPD52 increased in OSCC cells under hypoxia. However, the increase was independent of HIF transcription. Importantly, the observation was due to upregulation of mRNA stability by binding of mRNA to T-cell intercellular antigen (TIA) 1 and TIA-related protein (TIAR). Simultaneous knockdown of TPD52 and inhibition of HIF significantly reduced cell viability. In addition, the in vivo tumor-xenograft experiments showed that TPD52 acts as an autophagy inhibitor caused by a decrease in p62.Conclusions. This study showed that the expression of TPD52 increases in OSCC cells under hypoxia in a HIF-independent manner and plays an important role in the proliferation and survival of the cells in concordance with HIF, suggesting that novel cancer therapeutics might be led by TPD52 suppression.

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