Low Expression of Toll-like Receptor 4 Is Associated With Poor Prognosis in Bladder Cancer

Kusuhara, Yoshito; Daizumoto, Kei; Kawai, Kaichi; Hirayama, Kento; Kowada, Minoru; Shintani, Terumichi; Fukuhara, Yayoi; Dondoo, Tsogt-Ochir; Ozaki, Keisuke; Tsuda, Momoko; Fukawa, Tomoya; Nakatsuji, Hiroyoshi; Bando, Yoshimi; Uehara, Hisanori; Fukumori, Tomoharu; Takahashi, Masayuki; Kanayama, Hiro‐omi

doi:10.21873/anticanres.13166

Cited by 9 publications

(4 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A low level of TLR4 can effectively forecast poor outcomes for bladder cancer patients. The result is consistent with a previous report (Kusuhara et al, 2019). Moreover, the expression of TLR4 is lower in the elderly, high grade tumors, higher tumor stage, and progressive tumors.…”

Section: Discussionsupporting

confidence: 93%

Toll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis

Xia

Sun

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

BackgroundThe toll-like receptor 4 (TLR4) agonist, Bacille Calmette-Guérin, has exhibited gratifying effects in treating bladder cancer. The study aims to explore the expression pattern, prognostic value, and potential mechanism of TLR4 in bladder cancer.MethodsThe transcriptome file from the GSE13507 dataset in the Gene Expression Omnibus database and the promoter methylation file from the bladder cancer dataset in The Cancer Genome Atlas database were downloaded for analysis. The prognostic value of the TLRs was assessed by univariate Cox regression. Immunohistochemistry was applied to verify the expression of TLR4 in bladder cancer. The drug response is estimated through the R package “pRRophetic.” The CIBERSORT algorithm was carried out to estimate the infiltrating immune cells of samples. Gene Set Enrichment Analysis (GSEA) was performed to identify the pathways involved under varied TLR4 expression levels.ResultsTLR4 is decreased in tumor tissues compared with surrounding tumor tissues or normal tissue, which is also positively correlated to the overall survival rate (hazard ratio [HR] = 0.38) and cancer-specific survival rate (HR = 0.15) of patients with bladder cancer. Low expression of TLR4 is observed in tumors with malignant performance (high pathological grade, higher tumor stage, and progression). Patients with low TLR4 levels are more sensitive to gemcitabine rather than cisplatin. The promoter methylation level of TLR4 is positively associated with TLR4 expression (P < 0.001). The cg14629571 methylation site largely contributes to the overall methylation level. The CIBERSORT analysis shows that high TLR4 expression is associated with lower levels of plasma cells, M0 macrophages, and M1 macrophages. The GSEA results indicate that the TGF-β pathway and apoptosis are activated in high TLR4 bladder cancer, while G2M checkpoint and E2F targets pathways are enriched in low TLR4 bladder cancer.ConclusionThis research discusses the abnormal expression and prognostic value of TLR4 in bladder cancer. The TLR4 expression can effectively predict oncological outcomes and drug sensitivity of bladder cancer patients. TLR4 is also associated with infiltrating immune cell variation and cancer pathway dysregulation. The results provide a novel prognostic marker and potential drug targets for bladder cancer.

show abstract

Section: Discussionsupporting

confidence: 93%

Toll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis

Xia

Sun

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…In the future, we will have to experiment with other more accurate method such as 3D to investigate the status of invasion. In this study, we could not show the evidence to suggest which downstream signal pathways including growth factors and cytokines such as previously reported (47,48) are involved in cell proliferation, invasiveness, and so on.…”

Section: Discussioncontrasting

confidence: 86%

The Dual Function of Aryl Hydrocarbon Receptor in Bladder Carcinogenesis

Muto

et al. 2020

Anticancer Res

View full text Add to dashboard Cite

Background/Aim: Although Aryl hydrocarbon receptor (AhR) may be critical to several types of cancers, the function of AhR for carcinogenesis of bladder cancer (BC) is still inconclusive. We, therefore, sought to examine the involvement of AhR in bladder carcinogenesis. Materials and Methods: We examined the AhR expression of human BC and N-butyl-N-(4-hydroxybutyl)-induced bladder carcinogenesis in AhR-deficient mice. Results: There was a significantly higher expression of AhR in non-muscle-invasive BC compared to normal tissue and muscle-invasive BC (MIBC).The incidence of MIBC in AhR-deficient mice (87.5%) was significantly higher than wild-type mice (9.5%, p<0.01). In cell invasion assay, the induction of AhR signaling resulted in attenuation of BC cell invasiveness and proliferation. Conclusion: These results suggest that AhR may be essential for the initiation of carcinogenesis and attenuated the invasion of BC cells; this signaling may have a dual function in bladder carcinogenesis.

show abstract

“…On the other hand, the manipulation with these molecules might present an opportunity for the therapeutic impact onto the disease course. Kusuhara et al [9] arrived at a conclusion that lower expression of TLR4 correlates with poor prognosis of BC, with squamous differentiation of MIBC, lower cell proliferation, but higher invasiveness of cancer cells; depletion of TLR4 in low-stage BC cell lines increased the expression of cell morphology related genes, including keratin proteins and small proline-rich proteins. In our study, we found that in all BC cases tumor tissue had lower expression of TLR4 as compared to the unaffected portions of the urinary bladder.…”

Section: Discussionmentioning

confidence: 99%

“…Among TLRs the expression of TLR type 4 (TLR4) turned out to be the most prominent and relevant to the progression of BC and its prognosis [9]. TLR4 is present both on immune cells and BC cells [10], which makes it difficult to distinguish the dual role of TLR4 in cancer progression and anticancer immunity [11,12].…”

mentioning

confidence: 99%

Expression of TLR4 and major inflammatory cytokines in patients with bladder cancer of different grade and stage

Yakovlev

Gorbach

et al. 2023

Exp. oncol.

View full text Add to dashboard Cite

Summary. Background: The bladder cancer is immunogenic, and neoantigens generated by tumor cells trigger a notable immune response in the host. On the other hand, multiple immune escape mechanisms allow for avoiding the recognition by the host immune system. Toll-like receptor type 4 and inflammatory cytokines play major role in the immune response to bladder cancer. Aim: To assess the expression of TLR4 and the genes of major inflammatory cytokines in tumor cells and in unaffected tissue of the bladder. Materials and Methods: The pairs of samples from the urinary bladder tumor and unaffected adjacent tissue were obtained from 50 surgically treated patients with bladder cancer. The level of expression of TLR4, TGF-β1, INF-γ, TNF-α genes was evaluated by real-time polymerase chain reaction. Results: Bladder cancer cells are characterized by lower expression levels of TLR4, TGF-β1, INF-γ, TNF-α as compared to unaffected tissue. In patients with recurrent cancer, expression of TLR-4 and cytokines does not change both in tumor and in unaffected tissue of the bladder. Expression of TLR4 is identically low both in low- and high-grade cancer. Expression levels of the INF-γ and TNF-α are remarkably low in muscle-invasive cancer compared to the unaffected bladder tissue. The level of TGF-β1 in bladder cancer is comparable to the unaffected tissue of the bladder, while in the intact and metastatic lymph nodes it is significantly upregulated. Conclusion: Bladder cancer tissue differs from the unaffected part of the bladder wall in the level of TLR4, TGF-β1, INF-γ, TNF-α expression.

show abstract

Low Expression of Toll-like Receptor 4 Is Associated With Poor Prognosis in Bladder Cancer

Cited by 9 publications

References 24 publications

Toll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis

Toll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis

The Dual Function of Aryl Hydrocarbon Receptor in Bladder Carcinogenesis

Expression of TLR4 and major inflammatory cytokines in patients with bladder cancer of different grade and stage

Contact Info

Product

Resources

About