Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells

Park, Sang-Min; Hwang, Chae Young; Cho, Sung-Hwan; Lee, Daewon; Gong, Jeong-Ryeol; Lee, Soobeom; Nam, Sohee; Cho, Kwang-Hyun

doi:10.1111/febs.14773

Cited by 36 publications

(27 citation statements)

References 56 publications

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“…Interestingly, DUSP4 overexpression in CRC cell lines decreases their sensitivity to doxorubicin, a drug used to treat CRC (Kang et al, 2017). Moreover DUSP4 genetic inactivation increased the resistance to cetuximab, an epidermal growth factor receptor (EGFR)-blocking antibody, widely used and approved for treatment of metastatic CRC in cell lines and to another wellknown EGFR inhibitor, erlotinib (Park et al, 2019). Interestingly, those effects are also related to COX-2 expression, since DUSP4 was the highest induced gene in cetuximab-resistant CRC cells (Lu et al, 2016).…”

Section: Dual-specificity Mapk Phosphatasementioning

confidence: 99%

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

et al. 2020

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Colorectal cancer (CRC) is one of the most common and recurrent types of cancer, with high mortality rates. Several clinical trials and meta-analyses have determined that the use of pharmacological inhibitors of cyclooxygenase 2 (COX-2), the enzyme that catalyses the rate-limiting step in the synthesis of prostaglandins (PG) from arachidonic acid, can reduce the incidence of CRC as well as the risk of recurrence of this disease, when used together with commonly used chemotherapeutic agents. These observations suggest that inhibition of COX-2 may be useful in the treatment of CRC, although the current drugs targeting COX-2 are not widely used since they increase the risk of health complications. To overcome this difficulty, a possibility is to identify genes regulated by COX-2 activity that could give an advantage to the cells to form tumors and/or metastasize. The modulation of those genes as effectors of COX-2 may cancel the beneficial effects of COX-2 in tumor transformation and metastasis. A review of the available databases and literature and our own data have identified some interesting molecules induced by prostaglandins or COX-2 that have been also described to play a role in colon cancer, being thus potential pharmacological targets in colon cancer. Among those mPGES-1, DUSP4, and 10, Programmed cell death 4, Trop2, and many from the TGFb and p53 pathways have been identified as genes upregulated in response to COX-2 overexpression or PGs in colon carcinoma lines and overexpressed in colon tumor tissue. Here, we review the available evidence of the potential roles of those molecules in colon cancer in the context of PG/ COX signaling pathways that could be critical mediators of some of the tumor growth and metastasis advantage induced by COX-2. At the end, this may allow defining new therapeutic targets/drugs against CRC that could act specifically against tumor cells and would be effective in the prevention and treatment of CRC, lacking the unwanted side effects of COX-2 pharmacological inhibitors, providing alternative approaches in colon cancer.

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Section: Dual-specificity Mapk Phosphatasementioning

confidence: 99%

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

et al. 2020

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“…Before nearly 10 years, several studies had been established to make sure functional strategy of PHLDA1 in breast cancer and neuroblastoma, which was effector of aurora A kinase and led to cell death [32,33]. Apoptosis is a crucial phenomenon when cancer cell surfer from radio or chemical stimuli [34][35][36][37]. The suppression of apoptosis behavior has been explored in oral cancer [38].…”

Section: Ivyspringmentioning

confidence: 99%

High-matrix-stiffness induces promotion of hepatocellular carcinoma proliferation and suppression of apoptosis via miR-3682-3p-PHLDA1-FAS pathway

Yao

Niu

et al. 2020

J. Cancer

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Hepatocellular carcinoma (HCC) with malignant behaviors related to death causes distant metastasis and is the fourth primary cancer in the whole world, which has taken millions lives in Asian countries such as China. The novel miR-3682-3p involving high-expression-related poor prognosis in HCC tissues and cell lines indicate oncogenesis functions in vitro and in vivo. According to TCGA database, our group find several none-coding RNAs showing abnormal expression including miR-3682-3p, thus we originally confirmed the inhibition of proliferation and acceleration of apoptosis are enhanced in miR-3682-3p knock-down cell lines. Then, in nude mice transplantation assays, we found the suppressor behaviors, smaller nodules and lower speed of tumor expansion in model of injection of cell cultured and transfected shRNA-miR-3682-3p. A combination of databases (Starbase, Targetscan and MiRgator) illustrates miR-3682-3p targets PHLDA1, which shows negative correlation demonstrated by dual-luciferase reporter system. To make functional verification of PHLDA1, we upregulate the gene and rescue tests are established to confirm that miR-3682-3p suppresses PHLDA1 to promotion of cell growth. Rescue experiments finish making confirmation of relation of miR-3682-3p and PHLDA1 subsequently. Cirrhotic tissues illustrate strong correlation to higher miR-3682-3p and clinical features make the hint that high-extracellular-matrix-stiffness environment promotes such miRNA. Functional tests on different stiffness provide the proof of underlying mechanism. In conclusion, the overexpression of miR-3682-3p mediates PHLDA1 inhibition could impede apoptosis and elevate proliferation of HCC through high-extracellular-matrix-stiffness environment potentially.

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“…Systemic treatment of metastatic CRC usually involves chemotherapy backbone (fluoropyrimidines, oxaliplatin and irinotecan chemotherapies form) combined with biotherapy [4]. However, despite therapeutic advancements, the prognosis for metastatic CRC patients remains poor, with a median overall survival of 18-21 months [5]. Drug resistance is the main reason for the failure of chemotherapy in cancers.…”

Section: Introductionmentioning

confidence: 99%

Detection of genes responsible for cetuximab sensitization in colorectal cancer cells using CRISPR-Cas9

Yang

Yan

et al. 2020

Bioscience Reports

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Colorectal cancer (CRC) is a common malignant tumor in digestive tract with highly invasive and metastatic capacity. Drug sensitivity remains a significant obstacle to successful chemotherapy in CRC patients. This study aimed to explore genes related to cetuximab (CTX) sensitivity in CRC by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. Celigo image cytometer was used to detect suitable cells and optimal dosage of CTX. Inhibition rate of CTX on Caco-2 cells was evaluated by CCK-8 method before and after transfection. 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) was performed to explore suitable concentration of puromycin and multiplicity of infection (MOI). CRISPR-Cas9, sequencing data quality analysis and cell viability test were used for the selection of genes related to CTX sensitivity in CRC cells. Finally, the selected genes associated with CTX sensitivity in CRC cells were further validated by colony formation and CCK-8 assays. In this study, Caco-2 cells had a better prolificacy, and CTX 100 ug/ml exhibited a good inhibition trend on the 7th and 14th day of infection. MTT assay indicated that the minimum lethal concentration of puromycin was 2.5 μg/mL. Forty-six candidate genes were preliminarily screened via sequencing data quality analysis. Subsequently, we found that knockout of any of the four genes (MMP15, MRPL48, CALN1 and HADHB) could enhance CTX sensitivity in Caco-2 cells, which was further confirmed by colony formation assay. In summary, MMP15, MRPL48, CALN1 and HADHB genes are related to the mediation of CTX sensitivity in CRC.

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Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells

Cited by 36 publications

References 56 publications

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

High-matrix-stiffness induces promotion of hepatocellular carcinoma proliferation and suppression of apoptosis via miR-3682-3p-PHLDA1-FAS pathway

Detection of genes responsible for cetuximab sensitization in colorectal cancer cells using CRISPR-Cas9

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