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 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 Anti-EGFR-Coated Gold Nanoparticles In Vitro Carry 5-Fluorouracil to Colorectal Cancer Cells

Materials ◽  
2020 ◽  
Vol 13 (2) ◽  
pp. 375 ◽  
Author(s):  
Raquel B. Liszbinski ◽  
Graziela G. Romagnoli ◽  
Carolina M. Gorgulho ◽  
Caroline R. Basso ◽  
Valber A. Pedrosa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gold Nanoparticles ◽  
Cancer Cells ◽  
Cell Lines ◽  
Antineoplastic Agent ◽  
Physicochemical Characterization ◽  
Colorectal Cancer Cells ◽  
Induced Apoptosis ◽  
20 Nm

The aim of the current study is to present a strategy to improve the efficiency of 5-fluorouracil (5-FU), which is widely used as antineoplastic agent against solid tumors-based on the use of gold nanocarriers to overcome the resistance of colorectal cancer cells. 5-FU was loaded on gold nanoparticles (AuNP) coated with anti-EGFR antibodies in order to target them towards colorectal cancer cells that overexpress epidermal growth factor receptors (EGFR). Physicochemical characterization has shown that AuNP size was approximately 20 nm and that AuNP functionalization led to spherical nanoparticles. Flow cytometry allowed observing that some compounds synthesized by our research group have induced apoptosis/necrosis and impaired the proliferation of colon cancer cell lines ‘HCT-116′ and ‘HT-29′. The antibody/drug combination in AuNP (AuNP 5FU EGFR) has improved the apoptosis rate and impaired cell proliferation in both cell lines, regardless of the exposure time. Overall, these results have shown that AuNP functionalization with monoclonal antibodies focused on delivering 5-FU to tumor cells is an exciting strategy against colorectal cancer.

scholarly journals Epsilon-Globin HBE1 Enhances Radiotherapy Resistance by Down-Regulating BCL11A in Colorectal Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 498 ◽  
Author(s):  
Sang Yoon Park ◽  
Seon-Jin Lee ◽  
Hee Jun Cho ◽  
Jong-Tae Kim ◽  
Hyang Ran Yoon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cellular Damage ◽  
Sequencing Analysis ◽  
Ros Production ◽  
Γ Irradiation ◽  
Amino Terminal ◽  
Colorectal Cancer Cells ◽  
Radiation Induced

Resistance to radiotherapy is considered an important obstacle in the treatment of colorectal cancer. However, the mechanisms that enable tumor cells to tolerate the effects of radiation remain unclear. Moreover, radiotherapy causes accumulated mutations in transcription factors, which can lead to changes in gene expression and radiosensitivity. This phenomenon reduces the effectiveness of radiation therapy towards cancer cells. In the present study, radiation-resistant (RR) cancer cells were established by sequential radiation exposure, and hemoglobin subunit epsilon 1 (HBE1) was identified as a candidate radiation resistance-associated protein based on RNA-sequencing analysis. Then, compared to radiosensitive (RS) cell lines, the overexpression of HBE1 in RR cell lines was used to measure various forms of radiation-induced cellular damage. Consequently, HBE1-overexpressing cell lines were found to exhibit decreased radiation-induced intracellular reactive oxygen species (ROS) production and cell mortality. Conversely, HBE1 deficiency in RR cell lines increased intracellular ROS production, G2/M arrest, and apoptosis, and decreased clonogenic survival rate. These effects were reversed by the ROS scavenger N-acetyl cysteine. Moreover, HBE1 overexpression was found to attenuate radiation-induced endoplasmic reticulum stress and apoptosis via an inositol-requiring enzyme 1(IRE1)—Jun amino-terminal kinase (JNK) signaling pathway. In addition, increased HBE1 expression induced by γ-irradiation in RS cells attenuated expression of the transcriptional regulator BCL11A, whereas its depletion in RR cells increased BCL11A expression. Collectively, these observations indicate that the expression of HBE1 during radiotherapy might potentiate the survival of radiation-exposed colorectal cancer cells.

scholarly journals Silencing of HOTAIR Induced Apoptosis in Human Colorectal Cancer Cells through Up-Regulation of Bax and Down-Regulation of Bcl2

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Reza Dashtbozorgi ◽  
Maryam Tahmasebi-Birgani ◽  
Mohammad-Reza Hajjari ◽  
Amirnader Emami Razavi
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Expression Level ◽  
Altered Expression ◽  
Colorectal Cancer Cells ◽  
Apoptosis Markers ◽  
Induced Apoptosis ◽  
Human Colorectal Cancer Cells

: HOX transcript antisense RNA (HOTAIR), as a long noncoding RNA (lncRNA) is a highly cited transcript modulating variety of signaling pathways such as cell growth and apoptosis. Altered expression of HOTAIR has been reported in human cancers, which contributes with cancer progression and metastasis. Increased expression level of HOTAIR has been observed in colorectal cancer (CRC). It seems that dysregulation of HOTAIR may inhibit the apoptosis. The present study was aimed to evaluate the effect of HOTAIR silencing on expression of apoptosis markers Bax and Bcl2 using real-time polymerase chain reaction (PCR). The data showed that HOTAIR and Bcl2 are highly expressed in CRC cells while the expression level of Bax is low. Following siRNA treatment, Blc2 was downregulated but Bcl2 was upregulated. These findings suggest that HOTAIR silencing can promote apoptosis, and thus it can be considered as a promising strategy to kill cancer cells.

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 Knockdown of Mir-135b Sensitizes Colorectal Cancer Cells to Oxaliplatin-Induced Apoptosis Through Increase of FOXO1

2018 ◽  
Vol 48 (4) ◽  
pp. 1628-1637 ◽  
Author(s):  
Yan Qin ◽  
Longhai Li ◽  
Fang Wang ◽  
Xinyi Zhou ◽  
Yankui Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Pcr Analysis ◽  
Aberrant Expression ◽  
Colorectal Cancer Cells ◽  
Novel Strategy ◽  
Induced Apoptosis

Background/Aims: Aberrant expression of microRNAs (miRNAs) is found to be responsible for tumorigenesis, cancer development and chemoresistance. Although oxaliplatin is an effective chemotherapeutic drug for treatment of colorectal cancer (CRC), CRC cells can develop some mechanisms to evade oxaliplatin-induced cell death. It is urgent to explore the novel strategies to increase the chemosensitivity of CRC cells. Methods: QRT-PCR analysis was performed to detect the expression of miR-135b in CRC patients’ serum and CRC cell lines. MTT assays were used to evaluate the effect of anti-miR-135b on oxaliplatin-induced cell death in CRC cell lines. Western blot, flow cytometry and luciferase reporter assays were performed to evaluate the potential mechanism and pathway of anti-miR-135b-promoted apoptosis in oxaliplatin-treated CRC cells. Results: Significant upregulation of miR-135b was observed in CRC cell lines and CRC patients’ serum. Knockdown of miR-135b was found to sensitize colorectal cancer cells to oxaliplatin-induced cytotoxicity. Mechanically, knockdown of miR-135b increased the expression level of FOXO1 in CRC. As the downstream, the increased FOXO1 induced by anti-miR-135b promoted the expression of Bim and Noxa. Since Bim and Noxa act as key pro-apoptotic proteins in mitochondrial apoptosis, anti-miR-135b was able to enhance the oxaliplatin-induced apoptosis dependent on the anti-miR-135b/FOXO1 axis. Conclusions: Anti-miR-135b enhanced the anti-tumor effect of oxaliplatin on CRC. Combination with miR-135b antisense nucleotides may represent a novel strategy to sensitize CRC to oxaliplatin-based treatment.

scholarly journals Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine, DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4417
Author(s):  
Rabin Neupane ◽  
Saloni Malla ◽  
Mariam Sami Abou-Dahech ◽  
Swapnaa Balaji ◽  
Shikha Kumari ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Colon Cancer Cells ◽  
Apoptotic Pathway ◽  
Anticancer Efficacy ◽  
Colon Cell ◽  
Ic50 Values ◽  
Induced Apoptosis

A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.

Sign in / Sign up

Export Citation Format

Share Document