Aberrant up-regulation of iNOS/NO system is correlated with an increased abundance of Foxp3+ cells and reduced effector/memory cell markers expression during colorectal cancer: immunomodulatory effects of cetuximab combined with chemotherapy

Benkhelifa, Sarra; Rafa, Hayet; Belhadef, S.; Ait-Kaci, Hayat; Medjeber, Oussama; Belkhelfa, Mourad; Hetit, Sabah; Ait-Younes, S.; Launoit, Yvan de; Moralès, Olivier; Mahfouf, Hassen; Delhem, Nadira; Touil-Boukoffa, Chafia

doi:10.1007/s10787-019-00566-9

Cited by 12 publications

(11 citation statements)

References 55 publications

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“…Granados-Principal et al found that iNOS was highly expressed in triple-negative breast cancer [ 8 ]. Benkhelifa et al observed that significantly increased iNOS mRNA expression in metastatic tissues of colorectal cancer compared to primary tumors and unaffected mucosa [ 19 ]. Pereira et al showed that iNOS expressions were significantly increased in cancer-associated fibroblasts in pancreatic ductal adenocarcinoma [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway

Chu

Cao

Daokun³

et al. 2021

Journal of Immunology Research

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Inducible nitric oxide synthase (iNOS), accompanied with protumor and antitumor activity, has been studied in multiple cancers. However, the role of iNOS expression in osteosarcoma (OS) is far from being fully understood. In present work, iNOS levels were detected in OS tissues and cell lines. Colony formation assay, Transwell assay, and fow cytometer were used to assess proliferation, migration, invasion, and apoptosis abilities in vitro after iNOS inhibition. Western blotting determined the expressions of iNOS, MMP2, MMP9, C-MYC, Ki67, PCNA, and β-catenin. Mice transfected with OS cells were to evaluate tumor formation. IHC assay was to evaluate the expressions of iNOS and β-catenin in mice. The results showed that iNOS was upregulated in both OS tissues and cells compared with that in matched normal tissues or cells. And we found that proliferation, migration, and invasion numbers of OS cells were decreased, and apoptosis numbers of OS cells were increased after iNOS inhibition. MMP2, MMP9, C-MYC, Ki67, and PCNA levels were also reduced in OS cells treated with iNOS inhibition. Else, iNOS inhibition would suppress β-catenin expression in OS cells to regulate MMP2, MMP9, C-MYC, Ki67, and PCNA expressions. In addition, tumor formation, iNOS expression, and β-catenin expression were inhibited in mice transplanted with iNOS knockout OS cells. These results indicated that iNOS might be a potential therapeutic target for OS.

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Section: Discussionmentioning

confidence: 99%

iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway

Chu

Cao

Daokun³

et al. 2021

Journal of Immunology Research

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“…Growing evidence also proves that CAC is sustained and promoted by inflammatory signals from the surrounding microenvironment. 10 , 11 For example, it was reported that the proinflammatory mediators or signals, such as iNOS/NO system 12 and TLR4/NF‐κB signalling in TNF‐α/iNOS induction, 13 provided a mechanistic relationship between inflammation and cancer. Though these mechanisms by which chronic inflammation initiates colonic carcinogenesis are being investigated, many unanswered questions remain.…”

Section: Introductionmentioning

confidence: 99%

PRKAR2A‐derived circular RNAs promote the malignant transformation of colitis and distinguish patients with colitis‐associated colorectal cancer

Wan

Wang

et al. 2022

Clinical & Translational Med

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Background Emerging studies have proved that colonic inflammation caused by refractory inflammatory bowel disease (IBD) can initiate the colitis‐associated cancer (CAC), but the transition from inflammation to carcinoma is still largely unknown. Methods In this study, mouse colitis and CAC models were established, and the RNA‐seq by circRNA microarray was employed to identify the differentially expressed circRNAs and mRNAs in different comparisons (DSS vs. NC and AOM/DSS vs. DSS). The bioinformatics analyses were used to search the common characteristics in mouse colitis and CAC. Results The K‐means clustering algorithm packaged these differential expressed circRNAs into subgroup analysis, and the data strongly implied that mmu_circ_0001109 closely correlated to the pro‐inflammatory signals, while mmu_circ_0001845 was significantly associated with the Wnt signalling pathway. Our subsequent data in vivo and in vitro confirmed that mmu_circ_0001109 could exacerbate the colitis by up‐regulating the Jak‐STAT3 and NF‐kappa B signalling pathways, and mmu_circ_0001845 promoted the CAC transformation through the Wnt signalling pathway. By RNA blasting between mice and humans, the human RTEL1‐ and PRKAR2A‐derived circRNAs, which might be considered as homeotic circRNAs of mmu_circ_0001109 and mmu_circ_0001845, respectively, were identified. The clinical data revealed that RTEL1‐derived circRNAs had no clinical significance in human IBD and CAC. However, three PRKAR2A‐derived circRNAs, which had the high RNA similarities to mmu_circ_0001845, were remarkably up‐regulated in CAC tissue samples and promoted the transition from colitis to CAC. Conclusions Our results suggested that these human PRKAR2A‐derived circRNAs could be novel candidates for distinguishing CAC patients and predicted the prognosis of CAC.

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“…These changes are well known to be associated with inflammatory response as indicated by elevated tissue levels of nitrite, TNF‐α, and PGE 2 . Similarly, the levels of NO have been shown to be higher in CRC patients as compared to healthy controls (Benkhelifa et al, ). Both PGE 2 and TNF‐α have also been shown to contribute to tumor promotion and progression not only through pro‐inflammatory mechanisms but also through a crosstalk with Wnt/β‐catenin pathway (Hamiza et al, ; Jang et al, ; Stanilov, Dobreva, & Stanilova, ; Wang & DuBois, ).…”

Section: Discussionmentioning

confidence: 97%

“…Cancerous changes produced by DMH in the present study were accompanied by enhanced IR of inflammatory markers like COX‐2, iNOS, NF‐κB, and IL‐1β. Both COX‐2 and iNOS are enzymes that catalyze the formation of inflammatory mediators, namely, PGE 2 and NO, which have well‐established tumor‐promoting properties (Benkhelifa et al, ; Wang & DuBois, ). Elevated levels of both COX‐2 and iNOS have been reported in CRC specimens as compared to colon tissue from healthy controls (Benkhelifa et al, ; Wang & DuBois, ).…”

Section: Discussionmentioning

confidence: 99%

“…The COX pathway has an important role in neutrophil accumulation through generation of PGE 2 . Enhanced expression of COX‐2, production of PGE 2 , and upregulation of iNOS/NO have been shown to contribute to colorectal tumorigenesis and metastasis (Benkhelifa et al, ; Castellone, Teramoto, & Gutkind, ; Sinicrope & Gill, ). It is also interesting to note that COX‐2 has been identified as a therapeutic target for chemoprevention of CRC (Wallace, ).…”

Section: Discussionmentioning

confidence: 99%

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Artesunate suppresses inflammation and oxidative stress in a rat model of colorectal cancer

Kumar

Verma

Das

2019

Drug Development Research

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Anti‐inflammatory drugs are well known to reduce the risk of colon cancer and prophylactic use of such agents is gaining acceptance as a cancer prevention therapy. As artesunate, an antimalarial drug, has been shown to exhibit chemopreventive properties, the present study was carried out to evaluate its inhibitory effect on oxidative stress and inflammation in a rat model of colon carcinogenesis. A chemical carcinogen, 1,2‐dimethylhydrazine was injected twice at an interval of 1 week to induce preneoplastic lesions in the colon and the parameters indicating oxidative stress and inflammation were evaluated after 8 weeks. Artesunate (50 and 150 mg/kg) and aspirin (60 mg/kg) were administered orally throughout the study. Analysis of colon tissue revealed that both the drugs preserved histoarchitecture, inhibited cellular influx, decreased the levels of oxidative stress and inflammatory markers, downregulated cyclooxygenase‐2, inducible nitric oxide synthase, nuclear factor κB, and interleukin 1β in comparison to the experimental control. Suppression of oxidative stress and pro‐inflammatory signaling by both the drugs were found to contribute to inhibition of colon carcinogenesis. The protection afforded by these drugs was found to be comparable. Our study shows that like aspirin, use of artesunate could also reduce the risk of colon cancer and it has a potential for further evaluation for the treatment purpose.

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Aberrant up-regulation of iNOS/NO system is correlated with an increased abundance of Foxp3+ cells and reduced effector/memory cell markers expression during colorectal cancer: immunomodulatory effects of cetuximab combined with chemotherapy

Cited by 12 publications

References 55 publications

iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway

iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway

PRKAR2A‐derived circular RNAs promote the malignant transformation of colitis and distinguish patients with colitis‐associated colorectal cancer

Artesunate suppresses inflammation and oxidative stress in a rat model of colorectal cancer

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