scholarly journals A KLF4/PiHL/EZH2/HMGA2 regulatory axis and its function in promoting oxaliplatin-resistance of colorectal cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Xuan Deng ◽  
Fanyang Kong ◽  
Si Li ◽  
Haoqin Jiang ◽  
Liu Dong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
In Vivo Models ◽  
Akt Phosphorylation ◽  
New Class ◽  
H3k27me3 Level ◽  
Tumor Tissues ◽  
Signaling Axis ◽  
Induced Apoptosis

AbstractLong noncoding RNAs (lncRNAs) have emerged as a new class of regulatory molecules implicated in therapeutic resistance, yet the mechanisms underlying lncRNA-mediated oxaliplatin resistance in colorectal cancer (CRC) are poorly understood. In this study, lncRNA P53 inHibiting LncRNA (PiHL) was shown to be highly induced in oxaliplatin-resistant CRC cells and tumor tissues. In vitro and in vivo models clarified PiHL’s role in conferring resistance to oxaliplatin-induced apoptosis. PiHL antagonized chemosensitivity through binding with EZH2, repressing location of EZH2 to HMGA2 promoter, and downregulating methylation of histone H3 lysine 27 (H3K27me3) level in HMGA2 promoter, thus activating HMGA2 expression. Furthermore, HMGA2 upregulation induced by PiHL promotes PI3K/Akt phosphorylation, which resulted in increased oxaliplatin resistance. We also found that transcription factor KLF4 was downregulated in oxaliplatin-resistant cells, and KLF4 negatively regulated PiHL expression by binding to PiHL promoter. In vivo models further demonstrated that treatment of oxaliplatin-resistant CRC with locked nucleic acids targeting PiHL restored oxaliplatin response. Collectively, this study established lncRNA PiHL as a chemoresistance promoter in CRC, and targeting PiHL/EZH2/HMGA2/PI3K/Akt signaling axis represents a novel choice in the investigation of drug resistance.

scholarly journals miR-142-3p Suppresses Cell Growth by Targeting CDK4 in Colorectal Cancer

2018 ◽  
Vol 51 (4) ◽  
pp. 1969-1981 ◽  
Author(s):  
Xiangyu Zhu ◽  
Si-ping Ma ◽  
Dongxiang Yang ◽  
Yanlong Liu ◽  
Yong-peng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Growth ◽  
Tumor Cell ◽  
Nude Mice ◽  
Colony Formation ◽  
Tumor Cell Growth ◽  
Rt Pcr ◽  
Tumor Tissues

Background/Aims: Deregulation of microRNAs (miRNAs) has been associated with a variety of cancers, including colorectal cancer (CRC). Here, we investigated anomalous miR-142-3p expression and its possible functional consequences in primary CRC samples. Methods: The expression of miR-142-3p was measured by quantitative RT-PCR in 116 primary CRC tissues and adjacent non-tumor tissues. The effect of miR-142-3p up- or down-regulation in CRC-derived cells was evaluated in vitro by cell viability and colony formation assays and in vivo by growth assays in xenografted nude mice. Results: Using quantitative RT-PCR, we found that miR-142-3p was down-regulated in 78.4 % (91/116) of the primary CRC tissues tested when compared to the adjacent non-tumor tissues. We also found that the miR-142-3p mimic reduced in vitro cell viability and colony formation by inducing cell cycle arrest in CRC-derived cells, and inhibited in vivo tumor cell growth in xenografted nude mice. Inversely, we found that the miR-142-3p inhibitor increased the viability and colony forming capacity of CRC-derived cells and tumor cell growth in xenografted nude mice. In addition, we identified CDK4 as a potential target of miR-142-3p by predictions and dual-luciferase reporter assays. Concordantly, we found that miR-142-3p mimics and inhibitors could decrease and increase CDK4 protein levels in CRC-derived cells, respectively. Conclusion: From our results we conclude that miR-142-3p may act as a tumor suppressor in CRC and may serve as a tool for miRNA-based CRC therapy.

scholarly journals Single-cell RNA sequencing reveals distinct cellular factors for response to immunotherapy targeting CD73 and PD-1 in colorectal cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002503
Author(s):  
Miok Kim ◽  
Yong Ki Min ◽  
Jinho Jang ◽  
Hyejin Park ◽  
Semin Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
In Vivo Models ◽  
Single Cell Rna Sequencing ◽  
Tcr Diversity ◽  
Cancer Immunotherapies

BackgroundAlthough cancer immunotherapy is one of the most effective advanced-stage cancer therapies, no clinically approved cancer immunotherapies currently exist for colorectal cancer (CRC). Recently, programmed cell death protein 1 (PD-1) blockade has exhibited clinical benefits according to ongoing clinical trials. However, ongoing clinical trials for cancer immunotherapies are focused on PD-1 signaling inhibitors such as pembrolizumab, nivolumab, and atezolizumab. In this study, we focused on revealing the distinct response mechanism for the potent CD73 ectoenzyme selective inhibitor AB680 as a promising drug candidate that functions by blocking tumorigenic ATP/adenosine signaling in comparison to current therapeutics that block PD-1 to assess the value of this drug as a novel immunotherapy for CRC.MethodsTo understand the distinct mechanism of AB680 in comparison to that of a neutralizing antibody against murine PD-1 used as a PD-1 blocker, we performed single-cell RNA sequencing of CD45+ tumor-infiltrating lymphocytes from untreated controls (n=3) and from AB680-treated (n=3) and PD-1-blockade-treated murine CRC in vivo models. We also used flow cytometry, Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) models, and in vitro functional assays to validate our new findings.ResultsWe initially observed that the expressions of Nt5e (a gene for CD73) and Entpd1 (a gene for CD39) affect T cell receptor (TCR) diversity and transcriptional profiles of T cells, thus suggesting their critical roles in T cell exhaustion within tumor. Importantly, PD-1 blockade significantly increased the TCR diversity of Entpd1-negative T cells and Pdcd1-positive T cells. Additionally, we determined that AB680 improved the anticancer functions of immunosuppressed cells such as Treg and exhausted T cells, while the PD-1 blocker quantitatively reduced Malat1high Treg and M2 macrophages. We also verified that PD-1 blockade induced Treg depletion in AOM/DSS CRC in vivo models, and we confirmed that AB680 treatment caused increased activation of CD8+ T cells using an in vitro T cell assay.ConclusionsThe intratumoral immunomodulation of CD73 inhibition is distinct from PD-1 inhibition and exhibits potential as a novel anticancer immunotherapy for CRC, possibly through a synergistic effect when combined with PD-1 blocker treatments. This study may contribute to the ongoing development of anticancer immunotherapies targeting refractory CRC.

Schisandrin B Attenuates Colitis-Associated Colorectal Cancer through SIRT1 Linked SMURF2 Signaling

2021 ◽  
pp. 1-17
Author(s):  
Zhichen Pu ◽  
Weiwei Zhang ◽  
Minhui Wang ◽  
Maodi Xu ◽  
Haitang Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Growth ◽  
Protein Expression ◽  
Hct116 Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Schisandrin B ◽  
In Vivo Models

Colon cancer, a common type of malignant tumor, seriously endangers human health. However, due to the relatively slow progress in diagnosis and treatment, the clinical therapeutic technology of colon cancer has not been substantially improved in the past three decades. The present study was designed to investigate the effects and involved mechanisms of schisandrin B in cell growth and metastasis of colon cancer. C57BL/6 mice received AOM and dextran sulfate sodium. Mice in treatment groups were gavaged with 3.75–30 mg/kg/day of schisandrin B. Transwell chamber migration, enzyme-linked immunosorbent assay (ELISA), Western blot analysis, immunoprecipitation (IP) and immunofluorescence were conducted, and HCT116 cell line was employed in this study. Data showed that schisandrin B inhibited tumor number and tumor size in the AOD+DSS-induced colon cancer mouse model. Schisandrin B also inhibited cell proliferation and metastasis of colon cancer cells. We observed that schisandrin B induced SMURF2 protein expression and affected SIRT1 in vitro and in vivo. SMURF2 interacted with SIRT1 protein, and there was a negative correlation between SIRT1 and SMURF2 expressions in human colorectal cancer. The regulation of SMURF2 was involved in the anticancer effects of schisandrin B in both in vitro and in vivo models. In conclusion, the present study revealed that schisandrin B suppressed SIRT1 protein expression, and SIRT1 is negatively correlated with the induction of SMURF2, which inhibited cell growth and metastasis of colon cancer. Schisandrin B could be a leading compound, which will contribute to finding novel potential agents and therapeutic targets for colon cancer.

scholarly journals In Vitro and In Vivo Inhibitory Effect of Citrus Junos Tanaka Peel Extract against Oxidative Stress-Induced Apoptotic Death of Lung Cells

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1231
Author(s):  
Jin Woo Kim ◽  
Eun Hee Jo ◽  
Ji Eun Moon ◽  
Hanvit Cha ◽  
Moon Han Chang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protective Effect ◽  
Inhibitory Effect ◽  
Lung Cells ◽  
In Vivo Models ◽  
Citrus Junos ◽  
Induced Apoptosis ◽  
Peel Extract

Various stresses derived from both internal and external oxidative environments lead to the excessive production of reactive oxygen species (ROS) causing progressive intracellular oxidative damage and ultimately cell death. The objective of this study was to evaluate the protective effects of Citrus junos Tanaka peel extract (CE) against oxidative-stress induced the apoptosis of lung cells and the associated mechanisms of action using in vitro and in vivo models. The protective effect of CE was evaluated in vitro in NCI-H460 human lung cells exposed to pro-oxidant H2O2. The preventive effect of CE (200 mg/kg/day, 10 days) against pulmonary injuries following acrolein inhalation (10 ppm for 12 h) was investigated using an in vivo mouse model. Herein, we demonstrated the inhibitory effect of CE against the oxidative stress-induced apoptosis of lung cells under a highly oxidative environment. The function of CE is linked with its ability to suppress ROS-dependent, p53-mediated apoptotic signaling. Furthermore, we evaluated the protective role of CE against apoptotic pulmonary injuries associated with the inhalation of acrolein, a ubiquitous and highly oxidizing environmental respiratory pollutant, through the attenuation of oxidative stress. The results indicated that CE exhibits a protective effect against the oxidative stress-induced apoptosis of lung cells in both in vitro and in vivo models.

Transfection of PDCD5 sensitizes colorectal cancer cells to cisplatin-induced apoptosis in vitro and in vivo

2010 ◽  
Vol 649 (1-3) ◽  
pp. 120-126 ◽  
Author(s):  
Anning Yin ◽  
Yingan Jiang ◽  
Xianfeng Zhang ◽  
Juan Zhao ◽  
Hesheng Luo
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Colorectal Cancer Cells ◽  
Induced Apoptosis

scholarly journals Development of Preclinical Models to Understand and Treat Colorectal Cancer

2018 ◽  
Vol 31 (03) ◽  
pp. 199-204 ◽  
Author(s):  
Judith Sebolt-Leopold
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Tumors ◽  
Human Colorectal Cancer ◽  
Preclinical Models ◽  
In Vivo Models ◽  
Molecular Determinants ◽  
Experimental Therapies ◽  
Molecular Aberrations

AbstractThe establishment and validation of preclinical models that faithfully recapitulate the pathogenesis and treatment response of human colorectal cancer (CRC) is critical to expedient therapeutic advances in the clinical management of this disease. Integral to the application of precision medicine for patients diagnosed with metastatic CRC is the need to understand the molecular determinants of response for a given therapy. Preclinical models of CRC have proven invaluable in answering many of our basic questions relating to the molecular aberrations that drive colorectal tumor progression. This review will address the comparative merits and limitations of the broad spectrum of in vitro and in vivo models available for study of colorectal tumors and their response to experimental therapies.

scholarly journals N6-(2-hydroxyethyl)-Adenosine Induces Apoptosis via ER Stress and Autophagy of Gastric Carcinoma Cells In Vitro and In Vivo

2020 ◽  
Vol 21 (16) ◽  
pp. 5815
Author(s):  
Hongqing Xie ◽  
Xiaotong Li ◽  
Weiwei Yang ◽  
Liping Yu ◽  
Xiasen Jiang ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Er Stress ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Antineoplastic Effect ◽  
Tumor Tissues ◽  
Induced Apoptosis ◽  
Species Production

Gastric cancer is the most common malignant tumor of the digestive tract and is great challenge in clinical treatment. N6-(2-Hydroxyethyl)-adenosine (HEA), widely present in various fungi, is a natural adenosine derivative with many biological and pharmacological activities. Here, we assessed the antineoplastic effect of HEA on gastric carcinoma. HEA exerted cytotoxic effects against gastric carcinoma cells (SGC-7901 and AGS) in a dose and time-dependent manner. Additionally, we found that HEA induced reactive oxygen species production and mitochondrial membrane potential depolarization. Moreover, it could trigger caspase-dependent apoptosis, promoting intracellular Ca2+-related endoplasmic reticulum (ER) stress and autophagy. On the other hand, HEA could significantly inhibit the growth of transplanted tumors in nude mice and induce apoptosis of tumor tissues cells in vivo. In conclusion, HEA induced apoptosis of gastric carcinoma cells in vitro and in vivo, demonstrating that HEA is a potential chemotherapeutic agent for gastric carcinoma.

scholarly journals Synergistic antitumor effect of 5-fluorouracil with the novel LSD1 inhibitor ZY0511 in colorectal cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592093742
Author(s):  
Wen Peng ◽  
Huaqing Zhang ◽  
Shisheng Tan ◽  
Yan Li ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Effect ◽  
Underlying Mechanism ◽  
Synergistic Antitumor Effect ◽  
Anticancer Effects ◽  
Potential Marker ◽  
And Migration ◽  
Induced Apoptosis

Background: Lysine-specific histone demethylase 1 (LSD1) is a potential target of cancer therapy. In the present study, we aimed to investigate the combined antitumor activity of a novel LSD1 inhibitor (ZY0511) with 5-fluorouracil (5-FU) and elucidate the underlying mechanism in colorectal cancer (CRC). Methods: We evaluated LSD1 expression in CRC tissues from patients who received 5-FU treatment. The synergistic antitumor effect of 5-FU with ZY0511 against human CRC cells was detected both in vitro and in vivo. The underlying mechanism was explored based on mRNA sequencing (mRNA-seq) technology. Results: Overexpression of LSD1 was observed in human CRC tissues, and correlated with CRC development and 5-FU resistance. ZY0511, a novel LSD1 inhibitor, effectively inhibited CRC cells proliferation, both in vitro and in vivo. Notably, the combination of ZY0511 and 5-FU synergistically reduced CRC cells viability and migration in vitro. It also suppressed Wnt/β-catenin signaling and DNA synthesis pathways, which finally induced apoptosis of CRC cells. In addition, the combination of ZY0511 with 5-FU significantly reduced CRC xenograft tumor growth, along with lung and liver metastases in vivo. Conclusions: Our findings identify LSD1 as a potential marker for 5-FU resistance in CRC. ZY0511 is a promising candidate for CRC therapy as it potentiates 5-FU anticancer effects, thereby providing a new combinatorial strategy for treating CRC.

scholarly journals TRPC1 promotes the genesis and progression of colorectal cancer via activating CaM-mediated PI3K/AKT signaling axis

Oncogenesis ◽  
2021 ◽  
Vol 10 (10) ◽  
Author(s):  
Yang Sun ◽  
Chen Ye ◽  
Wen Tian ◽  
Wen Ye ◽  
Yuan-Yuan Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
Akt Signaling ◽  
Cycle Progression ◽  
Colorectal Tumorigenesis ◽  
Signaling Axis

AbstractTransient receptor potential canonical (TRPC) channels are the most prominent nonselective cation channels involved in various diseases. However, the function, clinical significance, and molecular mechanism of TRPCs in colorectal cancer (CRC) progression remain unclear. In this study, we identified that TRPC1 was the major variant gene of the TRPC family in CRC patients. TRPC1 was upregulated in CRC tissues compared with adjacent normal tissues and high expression of TRPC1 was associated with more aggressive tumor progression and poor overall survival. TRPC1 knockdown inhibited cell proliferation, cell-cycle progression, invasion, and migration in vitro, as well as tumor growth in vivo; whereas TRPC1 overexpression promoted colorectal tumor growth and metastasis in vitro and in vivo. In addition, colorectal tumorigenesis was significantly attenuated in Trpc1-/- mice. Mechanistically, TRPC1 could enhance the interaction between calmodulin (CaM) and the PI3K p85 subunit by directly binding to CaM, which further activated the PI3K/AKT and its downstream signaling molecules implicated in cell cycle progression and epithelial-mesenchymal transition. Silencing of CaM attenuated the oncogenic effects of TRPC1. Taken together, these results provide evidence that TRPC1 plays a pivotal oncogenic role in colorectal tumorigenesis and tumor progression by activating CaM-mediated PI3K/AKT signaling axis. Targeting TRPC1 represents a novel and specific approach for CRC treatment.

scholarly journals ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Chuangyu Wen ◽  
Huihui Wang ◽  
Xiaobin Wu ◽  
Lu He ◽  
Qian Zhou ◽  
...  
Keyword(s):  
Critical Role ◽  
Thioredoxin Reductase ◽  
Akt Pathway ◽  
Ros Generation ◽  
In Vivo Models ◽  
M Phase ◽  
Tumorigenesis And Progression ◽  
Induced Apoptosis

Abstract Novel drugs are urgently needed for gastric cancer (GC) treatment. The thioredoxin-thioredoxin reductase (TRX-TRXR) system has been found to play a critical role in GC tumorigenesis and progression. Thus, agents that target the TRX-TRXR system may be highly efficacious as GC treatments. In this study, we showed that chaetocin, a natural product isolated from the Chaetomium species of fungi, inhibited proliferation, induced G2/M phase arrest and caspase-dependent apoptosis in both in vitro and in vivo models (cell xenografts and patient-derived xenografts) of GC. Chaetocin inactivated TRXR-1, resulting in the accumulation of reactive oxygen species (ROS) in GC cells; overexpression of TRX-1 as well as cotreatment of GC cells with the ROS scavenger N-acetyl-L-cysteine attenuated chaetocin-induced apoptosis; chaetocin-induced apoptosis was significantly increased when GC cells were cotreated with auranofin. Moreover, chaetocin was shown to inactivate the PI3K/AKT pathway by inducing ROS generation; AKT-1 overexpression also attenuated chaetocin-induced apoptosis. Taken together, these results reveal that chaetocin induces the excessive accumulation of ROS via inhibition of TRXR-1. This is followed by PI3K/AKT pathway inactivation, which ultimately inhibits proliferation and induces caspase-dependent apoptosis in GC cells. Chaetocin therefore may be a potential agent for GC treatment.

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