The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinomaReport as inadecuate




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Journal of Experimental and Clinical Cancer Research

, 36:81

First Online: 21 June 2017Received: 24 February 2017Accepted: 15 June 2017DOI: 10.1186-s13046-017-0553-x

Cite this article as: Feng, X., Luo, Q., Zhang, H. et al. J Exp Clin Cancer Res 2017 36: 81. doi:10.1186-s13046-017-0553-x

Abstract

Background5-Fluorouracil 5-FU is a widely used drug for the therapy of cancer. However, the chemoresistance of tumor cells to 5-FU usually limits its clinical effectiveness. In this study, we explored the role of NLRP3 inflammasome in 5-FU resistance of oral squamous cell carcinoma OSCC.

MethodsThe mRNA and protein expression levels of NLRP3, Caspase1 and IL-1β in resected OSCC specimens or cell lines were measured respectively by quantitative real time-PCR qRT-PCR and western blot. NLRP3 and Ki-67 expression in paraffin-embedded OSCC tissues was determined by immunohistochemistry. The correlation between 5-FU treatment and the expression and activation of NLRP3 inflammasome was further examined by evaluating NLRP3 and IL-1β expression in OSCC cell lines without or with NLRP3 knocked down. Cell viabilities of OSCC cells were determined by the MTT assay. Apoptosis and intracellular reactive oxygen species ROS of OSCC cells induced by 5-FU were measured by the flow cytometer. The carcinogen-induced tongue squamous carcinoma mice model was established by continuous oral administration of 4-nitroquinoline 1-oxide in wild-type BALB-c, Nlrp3 and Caspase1 mice. Tumor incidence were observed and tumor area were evaluated.

ResultsIn the clinical analysis, expression and activation of NLRP3 inflammasome was clearly increased in OSCC tissues of patients who received 5-FU-based chemotherapy. Multivariate Cox regression analysis revealed that this high expression was significantly correlated with tumor stage and differentiation, and was associated with poor prognosis. Moreover, 5-FU treatment increased expression and activation of NLRP3 inflammasome in OSCC cells in a cell culture system and xenograft mouse model. Silencing of NLRP3 expression significantly inhibited OSCC cell proliferation and enhanced 5-FU-induced apoptosis of OSCC cells. Further investigation showed that intracellular ROS induced by 5-FU promoted the expression and activation of NLRP3 inflammasome and increased the production of interleukin IL-1β, which then mediated the chemoresistance. With the carcinogen-induced OSCC model, we found less and later tumor incidence in Nlrp3 and Caspase1 mice than wild-type mice. And greater decrease of tumor area was observed in the gene deficient mice treated with 5-FU.

ConclusionsOur findings suggest that NLRP3 inflammasome promoted 5-FU resistance of OSCC both in vitro and in vivo, and targeting the ROS-NLRP3 inflammasome-IL-1β signaling pathway may help 5-FU-based adjuvant chemotherapy of OSCC.

KeywordsNLRP3 inflammasome 5-Fluorouracil Oral squamous cell carcinoma Reactive oxygen species Chemotherapy Abbreviations4-NQO4-nitroquinoline 1-oxide

5-FU5-Fluorouracil

ASCApoptosis-associated speck-like protein containing a C-terminal caspase-recruitment domain

CIConfidence interval

DFSDisease-free survival

HRHazard ratio

MDSCMyeloid-derived suppressor cell

MTT3-4, 5-dimethylthiazol-2-yl-2, 5- diphenyltetrazolium bromide

NACN-acetylcysteine

NLRP3NLR family, pyrin domain containing 3

NLRsNucleotide-binding and oligomerization domain NOD-like receptors

OSOverall survival

OSCCOral squamous cell carcinoma

PRRsPattern recognition receptors

rIL-1βRecombinate interleukin-1β

ROSReactive oxygen species

shRNAShort hairpin RNA

TLRToll-like receptor





Author: Xiaodong Feng - Qingqiong Luo - Han Zhang - Han Wang - Wantao Chen - Guangxun Meng - Fuxiang Chen

Source: https://link.springer.com/







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