Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Wolska, Anna; Lech‐Marańda, Ewa; Robak, Tadeusz

doi:10.2478/s11658-008-0048-z

Cited by 64 publications

(45 citation statements)

References 113 publications

(100 reference statements)

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“…However, aberrant inactivation of NFkB through deletion of its essential modulator (NEMO, NF-kB essential modulator) triggers chronic inflammation and spontaneous HCC development (31). Likewise, TLRs, key players in innate immunity to pathogens and ubiquitously expressed on cancer cells, also play a complex role in regulating inflammation and tumorigenesis (35,36). Given the regulatory role in the activation of the TLR and NFkB pathways, we assume that MAP4K4 might represent a promising therapeutic target for chronic liver inflammation and associated cancer progression.…”

Section: Discussionmentioning

confidence: 99%

ShRNA-Targeted MAP4K4 Inhibits Hepatocellular Carcinoma Growth

Liu

Cai

Zhao

et al. 2011

Clinical Cancer Research

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Purpose: Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is overexpressed in many types of cancer. Herein, we aimed to investigate its expression pattern, clinical significance, and biological function in hepatocellular carcinoma (HCC).Experimental Design: MAP4K4 expression was examined in 20 fresh HCCs and corresponding nontumor liver tissues. Immunohistochemistry for MAP4K4 was performed on additional 400 HCCs, of which 305 (76%) were positive for hepatitis B surface antigens. The clinical significance of MAP4K4 expression was analyzed. MAP4K4 downregulation was performed in HCC cell lines HepG2 and Hep3B with high abundance of MAP4K4, and the effects of MAP4K4 silencing on cell proliferation in vitro and tumor growth in vivo were evaluated. Quantitative real-time PCR arrays were employed to identify the MAP4K4-regulated signaling pathways.Results: MAP4K4 was aberrantly overexpressed in HCCs relative to adjacent nontumor liver tissues. This overexpression was significantly associated with larger tumor size, increased histologic grade, advanced tumor stage, and intrahepatic metastasis, as well as worse overall survival and higher early recurrence rate. Knockdown of the MAP4K4 expression reduced cell proliferation, blocked cell cycle at S phase, and increased apoptosis. The antitumor effects of MAP4K4 silencing were also observed in vivo, manifested as retarded tumor xenograft growth. Furthermore, multiple tumor progression-related signaling pathways including JNK, NFkB, and toll-like receptors were repressed by MAP4K4 downregulation.Conclusions: MAP4K4 overexpression is an independent predictor of poor prognosis of HCC patients, and inhibition of its expression might be of therapeutic significance.

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Section: Discussionmentioning

confidence: 99%

ShRNA-Targeted MAP4K4 Inhibits Hepatocellular Carcinoma Growth

Liu

Cai

Zhao

et al. 2011

Clinical Cancer Research

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“…On the other hand, the anti-tumor roles of TLR4 have also attracted much attention. TLR ligands might enhance antigen presentation or induce the expression of target molecules, and bring into play the functions of immune response against tumor growth (29). However, what will occur in SW620 cell followed by TLR4 activation?…”

Section: Discussionmentioning

confidence: 99%

Activation of PAR2 or/and TLR4 promotes SW620 cell proliferation and migration via phosphorylation of ERK1/2

Zhou

Shucai³

et al. 2011

Oncol Rep

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Abstract. Protease-activated receptor 2 (PAR2) is a G-proteincoupled receptor and its activation has been associated with the pathogenetic progress in certain cancers. Toll-like receptor 4 (TLR4), one member of Toll-like receptors family, is mainly contributed to the innate immune response. However, recent studies have shown that TLR4 is aberrantly expressed in various types of carcinomas and may correlate with tumor progression. Previously, we reported that PAR2 could be expressed in human colon cancer cell line (SW620) and its activation by some stimulants was able to facilitate cell proliferation and migration. In our recent preliminary experiment, it was found that SW620 cells also had TLR4 expression. Thus, we considered that PAR2 and TLR4 could have some collaborative roles in SW620 cells. In the current study, the cross-inducible expression of PAR2 and TLR4 on SW620 cells was investigated, and the functional roles of their activation on the behavior of SW620 cells were evaluated. It was found that activation of PAR2 with PAR2-AP (PAR2 agonist, 100 μM) enhanced TLR4 releasement and vice versa. The activation of PAR2 or TLR4 (with LPS, 100 ng/ml) could promote SW620 cell proliferation and migration, and the phosphorylation of ERK1/2 but not p38MAPK, as well as the expression of interleukin 8 (IL-8) and tissue factor (TF). Whereas the caspase-7 expression was decreased under PAR2 or TLR4 activation. Furthermore, ERK1/2 inhibitor (U0126, at 10 μM) could intervene in all regulating effects of PAR2 or/and TLR4. Collectively, this study demonstrated that both PAR2 and TLR4 activation on SW620 cells can trigger the phosphorylation of ERK1/2, regulate the expression of IL-8, TF and caspase-7, thereby promote the proliferation and migration of cells.

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“…More evidence indicated that TLR signaling could enhance the anti-cancer immunity and the molecules involved in this pathway were often used as targets for therapy against cancer, although there were reports that expression of TLR could lead to tumor progression (Wolska et al, 2009). Many TLR agonists were proved to be helpful for the treatments of various kinds of cancer (Salaun et al, 2006;Zhang et al, 2009;Cheng and Xu, 2011;Lin et al, 2011;Zhang et al, 2011), and TLR5 agonist was reported to result in significant tumor regression (Rhee et al, 2008).…”

Section: Discussionmentioning

confidence: 99%