scholarly journals Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 386 ◽  
Author(s):  
Hiroshi Sugano ◽  
Yoshihiro Shirai ◽  
Takashi Horiuchi ◽  
Nobuhiro Saito ◽  
Yohta Shimada ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Cytotoxic Agents ◽  
Migration And Invasion ◽  
Nafamostat Mesilate ◽  
Tumor Invasiveness ◽  
Radiation Induced ◽  
Induced Apoptosis

Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC.

scholarly journals Downregulation of miR-423-5p Contributes to the Radioresistance in Colorectal Cancer Cells

2021 ◽  
Vol 10 ◽  
Author(s):  
Yuanyuan Shang ◽  
Lingfei Wang ◽  
Zhe Zhu ◽  
Wei Gao ◽  
Dan Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Radiation Treatment ◽  
Locally Advanced ◽  
Altered Expression ◽  
Colorectal Cancer Cells ◽  
Radiation Induced ◽  
Induced Apoptosis

Resistance to radiotherapy is the main reason causing treatment failure in locally advanced rectal cancer. MicroRNAs (miRNAs) have been well demonstrated to regulate cancer development and progression. However, how miRNAs regulate radiotherapy resistance in colorectal cancer remains unknown. Herein, we established two human colorectal cancer cell lines resistant to radiotherapy, named HCT116-R and RKO-R, using the strategy of fractionated irradiation. The radioresistant phenotypical changes of the two cell lines were validated by cell viability assay, colony formation assay and apoptosis assay. The miRNA expression profilings of HCT116-R and RKO-R were determined using RNA-seq analyses, and further confirmed by quantitative real-time PCR. Multiple miRNAs, including miR-423-5p, miR-7-5p, miR-522-3p, miR-3184-3p, and miR-3529-3p, were identified with altered expression in both of the radiotherapy-resistant cells, compared to the parental cells. The downregulation of miR-423-5p was further validated in the rectal cancer tissues from radiotherapy-resistant patients. Silencing of miR-423-5p in parental HCT116 and RKO cells decreased the sensitivity to radiation treatment, and inhibited the radiation-induced apoptosis. In consistence, overexpression of miR-423-5p in HCT116-R and RKO-R cells partially rescued their sensitivity to radiotherapy, and promoted the radiation-induced apoptosis. Bcl-xL (Bcl-2-like protein 1) was predicted to be a potential target gene for miR-423-5p, and miR-423-5p/Bcl-xL axis could be a critical mediator of radiosensitivity in colorectal cancer cells. The current finding not only revealed a novel role of miR-423-5p in regulating the radiosensitivity in colorectal cancer, but also suggested miR-423-5p as a molecular candidate for combination therapy with radiation to treat colorectal cancer.

scholarly journals Correction: Hiroshi Sugano et al. Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells. Cancers 2018, 10, 386

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 335
Author(s):  
Hiroshi Sugano ◽  
Yoshihiro Shirai ◽  
Takashi Horiuchi ◽  
Nobuhiro Saito ◽  
Yohta Shimada ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Nafamostat Mesilate ◽  
Invasive Ability ◽  
Colorectal Cancer Cells ◽  
Radiation Induced ◽  
Published Paper

The authors would like to make a correction to their published paper [...]

scholarly journals PARP Inhibitor Olaparib Enhances the Efficacy of Radiotherapy on Xrcc2-deficient Colorectal Cancer Cells

2021 ◽  
Author(s):  
changjiang Qin ◽  
Zhi-Yu Ji ◽  
Er-Tao Zhai ◽  
Kai-Wu Xu ◽  
Quan-Ying Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Parp Inhibitor ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Clonogenic Survival ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Abstract Background: Loss of XRCC2 compromises DNA damage repairs, and induced DNA damage burdens may increase the reliance on PARP-dependent DNA repairs of cancer cells to render cell susceptibility to PARP inhibitor therapy. Here, we study if XRCC2 loss sensitizes colorectal cancer(CRC) to PARP inhibitor in combination with radiotherapy (RT).Methods: The relationships between the expression of XRCC2 and PARP with patient outcome were investigated in 167 patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiotherapy (neoCRT). The in vitro radiosensitizing effects of olaparib were tested in XRCC2-deficient CRC using a clonogenic survival assay, determination of γH2AX foci, and measurement of β-galactosidase activity. An in vivo mouse xenograft model was used to determine the effect of olaparib on sensitization of tumors to ionizing radiation (IR).Results: High levels of XRCC2 or PARP1 were significantly associated with poor overall survival (OS) in patients with LARC who received neoCRT, co-expression analyses found low PARP1 and low XRCC2 expression have better OS. Our in vitro experiments indicated that olaparib+IR reduced clonogenic survival, increased persistent DNA damage, and prolonged cell cycle arrest and senescence in XRCC2-deficient cells relative to wild-type cells. Furthermore, our mouse xenograft experiments indicated that RT+olaparib had greater anti-tumor effects and led to long-term remission in mice with XRCC2-deficient tumors.Conclusions: XRCC2-deficient CRC acquire high sensitivity to PARP inhibition after IR treatment. Our preclinical findings provide a rationale for the use of Olaparib as a radiosensitizer for treatment of XRCC2-deficient CRC.

scholarly journals O11: MYOFERLIN: A NOVEL BIOMARKER OF RADIOSENSITIVITY IN LOCALLY ADVANCED RECTAL CANCER

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
H Fowler ◽  
P Sutton ◽  
D Bowden ◽  
J Parsons ◽  
D Vimalachandran
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Cancer Cells ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Radiation Doses ◽  
Clonogenic Assays ◽  
Colorectal Cancer Cells

Abstract Introduction Our proteomic data has validated that high levels of the protein myoferlin confers poorer response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Myoferlin plays a role in membrane repair and VEGF signal transduction, and is associated with worse prognosis in numerous other epithelial cancers. We aim to assess the impact of myoferlin on the radiosensitivity of rectal cancer. Method Clonogenic assays were performed using immortalised colorectal cancer cells (HCT116,HT29,LIM,MDST8) to assess survival at escalating radiation doses following knockdown with myoferlin siRNA or a small molecular inhibitor(WJ460). 3D models (spheroids) were used to examine the effect of WJ460 on tumour growth. Result Quantification of myoferlin using immunoblotting demonstrated that MDST8 and LIM were higher expressors than HCT116 and HT29. Higher levels correlated with increasing radio-resistance as calculated by colony formation efficiency (CFE). Using clonogenic assays, cells treated with myoferlin siRNA or WJ460 demonstrated increased radiosensitivity compared to controls across all radiation doses, most significantly at 4Gy. Treatment of spheroids with WJ460 significantly reduced growth compared to controls at all radiation doses (p<0.05), with WJ460 limiting growth considerably more than treatment with the current gold standard 5-FU. HCT116 spheroid volume day 15; WJ460 4.96um3,5-FU 6.74um3,DMSO 24.9um3. Conclusion Inhibition of myoferlin is associated with increased radiosensitivity of colorectal cancer cells, and treatment with a small molecular inhibitor significantly reduces growth in spheroid models. Further work is required further validate its potential use as a biomarker in locally advanced rectal cancer. Take-home message We have found that myoferlin is a protein associated with poor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Manipulation of this protein sensitises the cancer cells to radiotherapy.

scholarly journals Pals1 prevents Rac1-dependent colorectal cancer cell metastasis by inhibiting Arf6

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Simona Mareike Lüttgenau ◽  
Christin Emming ◽  
Thomas Wagner ◽  
Julia Harms ◽  
Justine Guske ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Scaffolding Protein ◽  
Migration And Invasion ◽  
Tight Junction Formation ◽  
Cell Metastasis ◽  
Colorectal Cancer Cells

AbstractLoss of apical-basal polarity and downregulation of cell-cell contacts is a critical step during the pathogenesis of cancer. Both processes are regulated by the scaffolding protein Pals1, however, it is unclear whether the expression of Pals1 is affected in cancer cells and whether Pals1 is implicated in the pathogenesis of the disease.Using mRNA expression data and immunostainings of cancer specimen, we show that Pals1 is frequently downregulated in colorectal cancer, correlating with poorer survival of patients. We further found that Pals1 prevents cancer cell metastasis by controlling Rac1-dependent cell migration through inhibition of Arf6, which is independent of the canonical binding partners of Pals1. Loss of Pals1 in colorectal cancer cells results in increased Arf6 and Rac1 activity, enhanced cell migration and invasion in vitro and increased metastasis of transplanted tumor cells in mice. Thus, our data reveal a new function of Pals1 as a key inhibitor of cell migration and metastasis of colorectal cancer cells. Notably, this new function is independent of the known role of Pals1 in tight junction formation and apical-basal polarity.

scholarly journals PRMT1 enhances oncogenic arginine methylation of NONO in colorectal cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Xin-Ke Yin ◽  
Yun-Long Wang ◽  
Fei Wang ◽  
Wei-Xing Feng ◽  
Shao-Mei Bai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Locally Advanced ◽  
Xenograft Model ◽  
Arginine Methylation ◽  
Mass Spectrometry Analysis ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Potential Marker

AbstractArginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.

LncRNA FTX Promotes Colorectal Cancer Cells Migration and Invasion by miRNA-590-5p/RBPJ Axis

2021 ◽  
Author(s):  
Guo-Qun Chen ◽  
Zhi-Ming Liao ◽  
Jiao Liu ◽  
Fang Li ◽  
Da Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Migration And Invasion ◽  
Colorectal Cancer Cells
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