Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-κB pathways in the oral squamous cell carcinoma microenvironment

Han, Shengwei; Xu, Wenguang; Wang, Zhiyong; Qi, Xin; Wang, Yufeng; Ni, Yajuan; Shen, Hao; Hu, Qingang; Han, Wei

doi:10.18632/oncotarget.9329

Cited by 64 publications

(47 citation statements)

References 39 publications

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“…38 Tumor hypoxia has been widely recognized as a major factor for chemoresistance. 11,39 So far, many attempts have been made to enhance the efficacy of Pt by using adjuvants, drug combinations, and nanomedicine systems. For instance, survivin inhibitor YM155 and 3′,4′,5′,5,7-pentamethoxyflavone were shown to have the ability to sensitize cancer cells to CDDP.…”

Section: Discussionmentioning

confidence: 99%

“…10 In accordance with previous reports, our group has also demonstrated that tumor hypoxia promotes OSCC resistance to the treatment of CDDP, with hypoxia inducible factor-1α (HIF-1α) acting as a key mediator. 11,12 Tumor microenvironment is a double-edged sword, because facts have proved that these special endogenous properties inside the tumor can be applied to trigger the release of cancer therapeutics. 13 Vascular abnormalities and tumor metabolic activity seek increased glycolysis.…”

Section: Introductionmentioning

confidence: 99%

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Antitumor effect of a Pt-loaded nanocomposite based on graphene quantum dots combats hypoxia-induced chemoresistance of oral squamous cell carcinoma

Zheng¹,

Yin²,

Cai³

et al. 2018

IJN

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Background Tumor microenvironment plays an important role in the chemoresistance of oral squamous cell carcinoma (OSCC). Hypoxia in the microenvironment is one of the important factors that contributes to OSCC chemoresistance; therefore overcoming hypoxia-mediated chemoresistance is one of the great challenges in clinical practice. Methods In this study, we developed a drug delivery system based on Pt-loaded, polyethylene glycol-modified graphene quantum dots via chemical oxidation and covalent reaction. Results Our results show that synthesized polyethylene glycol-graphene quantum dots-Pt (GPt) is about 5 nm in diameter. GPt sensitizes OSCC cells to its treatment in both normoxia and hypoxia conditions. Inductively coupled plasma-mass spectrometry assay shows that GPt enhances Pt accumulation in cells, which leads to a notable increase of S phase cell cycle arrest and apoptosis of OSCC cells in both normoxia and hypoxic conditions. Finally, compared with free cisplatin, GPt exhibits a strong inhibitory effect on the tumor growth with less systemic drug toxicity in an OSCC xenograft mouse tumor model. Conclusion Taken together, our results show that GPt demonstrates superiority in combating hypoxia-induced chemoresistance. It might serve as a novel strategy for future microenvironment-targeted cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antitumor effect of a Pt-loaded nanocomposite based on graphene quantum dots combats hypoxia-induced chemoresistance of oral squamous cell carcinoma

Zheng¹,

Yin²,

Cai³

et al. 2018

IJN

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“…TLR-9/MyD88 signaling pathway plays an important role in hypoxia and inflammatory responses, the expression of HIF-1α and VEGF (14), differentiation and activation of immune cells (15), and release of inflammatory factors such as IL-6 and TNF-α (16). In addition, TLR-9/MyD88 signaling pathway can mediate the transcription of NF-κB, whereas upstream promoter region of NF-κB contains HIF-1α binding site, which can affect the transcription and expression of HIF-1α, so NF-κB can participate in HIF-1α-regulated tumor cell proliferation and apoptosis and other biological activities (8,17).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor-9 in hypoxic nasopharyngeal carcinoma cells and its correlation with cell proliferation and apoptosis

2017

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Abstract. The purpose of this study was to investigate the correlation between the expression of Toll-like receptor-9 (TLR-9) and cell proliferation and apoptosis in hypoxic nasopharyngeal carcinoma cells. Human nasopharyngeal carcinoma cell line HNE-1 (EBV positive) and CNE-1 (EBV negative) were used. Cells were divided into normal control group, hypoxia group and hyperoxia group. Hypoxic conditions were 5% CO 2 and 0.01% partial pressure of oxygen, hyperoxia conditions were 5% CO 2 and 10% partial pressure of oxygen. Reverse transcription-PCR (RT-PCR) and western blot analysis were used to detect the expression of TLR-9 mRNA and protein at 6, 12 and 24 h after the beginning of cell culture. MTT assay was used to detect the cell proliferation rate and flow cytometry was used to detect cell apoptosis rate. Expression levels of TLR-9 mRNA and protein in hypoxia group reached the peak at 12 h after the beginning of cell culture, and were significantly higher than those of hyperoxia group at all time-points, expression levels of TLR-9 mRNA and protein of control group were the lowest, difference between groups were all statistically significant (P<0.05). No significant changes in expression levels of TLR-9 mRNA and protein were found in control group and hyperoxia group between different timepoints (P>0.05). Compared with the other two groups, cell proliferation rate was gradually decreased and apoptotic rate was gradually decreased in hypoxia group, significant differences were found between hypoxia group, and control group and hyperoxia group (P<0.05), no significant differences were found between control group and hyperoxia group (P>0.05).In conclusion, TLR-9 was highly expressed in hypoxic nasopharyngeal carcinoma cells regulating cell proliferation and apoptosis, which may be an important mechanism of tumorigenesis and a potential target for intervention therapy.

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“…HIF-1alpha regulates CAIX under hypoxic conditions (12). TLR activation stimulates the expression of HIF-1alpha through NF-jB -signaling in oral cancer, (13) while studies in breast and brain cancers indicated upregulation of TLR9 expression in hypoxia via HIF-1alpha (14), suggesting cross talk between TLR and HIF-1alpha signaling, i.e. innate immunity response and hypoxia.…”

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confidence: 99%

Toll‐like receptors 2, 4 and 9 and hypoxia markers HIF‐1alpha and CAIX in pancreatic intraepithelial neoplasia

Leppänen

Helminen

Huhta

et al. 2018

APMIS

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Pancreatic cancer arises from precursor lesions called pancreatic intraepithelial neoplasia (PanIN) characterized by inflammatory microenvironment. In pancreatic cancer, strong innate immunity and hypoxia responses are typical. Occurrence and relationship of these responses in human PanINs is unknown. We have studied the expression of toll‐like receptors (TLR) TLR2, TLR4 and TLR9, and hypoxia markers HIF‐1alpha and Carbonic anhydrase IX (CAIX) in normal and inflamed pancreatic ducts, in PanINs and in cancers. The samples of 69 surgically resected pancreatic ductal adenocarcinoma patients were stained using immunohistochemistry. We found TLR2, TLR9, HIF‐1alpha and CAIX to be prominently expressed in pancreatic intraepithelial neoplasia. Expression of TLR2 showed a linear increase from PanIN1 to PanIN3, while the highest TLR4 expression was detected in inflamed ducts, and TLR9 expression in PanIN1 lesions. Within the PanIN1‐group, nuclear HIF‐1alpha correlated with membranous and cytoplasmic TLR2 expression (ρ = 0.982 and 0.815; p < 0.001 and p = 0.025, respectively), and in the PanIN2‐group nuclear HIF‐1alpha correlated with nuclear TLR9 expression 0.636, p = 0.026). Our findings show that the expression of TLRs 2, 4 and 9, and hypoxia markers HIF‐1alpha and CAIX is abnormal in pancreatic intraepithelial neoplasia suggesting that both the innate immunity activation and hypoxia response are involved in early pancreatic carcinogenesis. However, these processes might be independent.

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Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-κB pathways in the oral squamous cell carcinoma microenvironment

Cited by 64 publications

References 39 publications

Antitumor effect of a Pt-loaded nanocomposite based on graphene quantum dots combats hypoxia-induced chemoresistance of oral squamous cell carcinoma

Antitumor effect of a Pt-loaded nanocomposite based on graphene quantum dots combats hypoxia-induced chemoresistance of oral squamous cell carcinoma

Toll-like receptor-9 in hypoxic nasopharyngeal carcinoma cells and its correlation with cell proliferation and apoptosis

Toll‐like receptors 2, 4 and 9 and hypoxia markers HIF‐1alpha and CAIX in pancreatic intraepithelial neoplasia

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