Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases

Ishiguro, Taro; Ávila, Héctor Martínez; Lin, Shiaw-Yih; Nakamura, Tõru; Yamamoto, Masayoshi; Boyd, Douglas D.

doi:10.1038/sj.bjc.6605536

Cited by 17 publications

(12 citation statements)

References 27 publications

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“…CLCN4 has been implicated in the development of colon cancer, and higher CLCN4 expression has been observed in Sirt3-deficient mice (Fig. 3f ) 25 . Consistently, the Sirt3 target protein, FOXO3a, was downregulated in Sirt3-deficient mice (Fig.…”

Section: Resultsmentioning

confidence: 92%

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Crosstalk between gut microbiota and Sirtuin-3 in colonic inflammation and tumorigenesis

et al. 2018

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Colorectal cancer (CRC) is a disease involving a variety of genetic and environmental factors. Sirtuin-3 (Sirt3) is expressed at a low level in cancer tissues of CRC, but it is unclear how Sirt3 modulates colonic tumorigenesis. In this study, we found that gut microbiota play a central role in the resistance to CRC tumor formation in wild-type (WT) mice through APC (Adenomatous Polyposis Coli)-mutant mouse microbiota transfer via Wnt signaling. We also found that Sirt3-deficient mice were hypersusceptible to colonic inflammation and tumor development through altered intestinal integrity and p38 signaling, respectively. Furthermore, susceptibility to colorectal tumorigenesis was aggravated by initial commensal microbiota deletion via Wnt signaling. Mice with Sirt3-deficient microbiota transfer followed by chemically induced colon tumorigenesis had low Sirt3 expression compared to WT control microbiome transfer, mainly due to a decrease in Escherichia/Shigella, as well as an increase in Lactobacillus reuteri and Lactobacillus taiwanensis. Collectively, our data revealed that Sirt3 is an anti-inflammatory and tumor-suppressing gene that interacts with the gut microbiota during colon tumorigenesis.

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Section: Resultsmentioning

confidence: 92%

“…CLCN4 has been shown to enhance colon cancer migration and metastasis. CLCN4 has been proposed as a risk factor for colon cancer, but its role in the early stages of colon cancer is unknown 25 . In summary, CLCN4 is critical for Sirt3-microbiome coordination with a tumor-suppressing effect, but further study is needed.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between gut microbiota and Sirtuin-3 in colonic inflammation and tumorigenesis

et al. 2018

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“…Although acidification is mediated by a V-type proton ATPase, it has been known that a parallel anion pathway conducted by chloride channels is also important to allow bulk proton transport (46). Thus, we examined the expression pattern of several chloride channels implicated in cancer metastasis (47)(48)(49). We found that Clca1, Clca5, and Clc-4 were highly expressed in B16-F10 cells compared to B16 cells ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 98%

The a3 Isoform Vacuolar Type H+-ATPase Promotes Distant Metastasis in the Mouse B16 Melanoma Cells

Nishisho

Hata

Nakanishi

et al. 2011

Molecular Cancer Research

133

128

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Accumulating evidence indicates that the acidic microenvironments critically influence malignant behaviors of cancer including invasiveness, metastasis, and chemoresistance. Because the vacuolar-type H þ -ATPase (V-ATPase) has been shown to cause extracellular acidification by pumping protons, we studied the role of V-ATPase in distant metastasis. Real-time PCR analysis revealed that the high-metastatic B16-F10 melanoma cells strongly expressed the a3 isoform V-ATPase compared to the low-metastatic B16 parental cells. Consistent with this, B16-F10 cells created acidic environments in lung metastases by acridine orange staining and strong a3 V-ATPase expression in bone metastases by immunohistochemistry. Immunocytochemical analysis showed B16-F10 cells expressed a3 V-ATPase not only in cytoplasm but also plasma membrane, whereas B16 parental cells exhibited its expression only in cytoplasm. Of note, knockdown of a3 V-ATPase suppressed invasiveness and migration with reduced MMP-2 and MMP-9 expression in B16-F10 cells and significantly decreased lung and bone metastases, despite that tumor growth was not altered. Importantly, administration of a specific V-ATPase a3 inhibitor FR167356 reduced bone metastasis of B16-F10 cells. These results suggest that a3 V-ATPase promotes distant metastasis of B16-F10 cells by creating acidic environments via proton secretion. Our results also suggest that inhibition of the development of cancer-associated acidic environments by suppressing a3 V-ATPase could be a novel therapeutic approach for the treatment of cancer metastasis. Mol Cancer Res; 9(7); 845-55. Ó2011 AACR.

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“…The functions of Ca2+-activated chloride channel include governing cellular ion fluxes and regulating cell volume ( 23 ). There is substantial evidence that cell migration is facilitated by the function of chlo-ride channels ( 3 , 6 , 24 ). The process of cell migration comprises cell swelling at the leading edge and subsequent cell shrinkage at the rear part of the cell ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

ANO1 as a marker of oral squamous cell carcinoma and silencing ANO1 suppresses migration of human scc-25 cells

Zhang²,

Hong³

2014

Med Oral

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Objectives: The purpose of this study is to confirm that ANO1 correlates with occurrence and metastasis of OSCC. Study Design: Immunohistochemistry was used to detect the expression of ANO1 in 160 specimens of OSCC and normal tissues. Lentiviral silencing ANO1 was used in scc-25 cell line to study the cell migration and cell detachment. Results: Immunohistochemical staining revealed that ANO1 was expressed in a large majority (132 out of 160, 82.5%) of OSCC specimens and that the rate of ANO1 expression in OSCC was significantly higher than that of normal tissue (P<0.05); The rate of ANO1 expression was higher in metastatic tumors than in non-metastatic tumors, and the difference was significant (P<0.05). The results of cell migration assay showed that the percentage of cells through the membrane was 26.61 ±0.81 in assay group, and 54.26 ±3.74 in control group, respectively (t=-16.22,P<0.0001). The results of cell detachment assay showed that the percentage of cells detachment was 37.42 ±0.90 in assay group, and 87.38 ±1.59 in control group, respectively (t=-62.34, P<0.0001). The results of wound healing assay showed the assay group had a reduced migration rate compared with the control group in 32 h (F=1038.78, P<0.0001). Wound closure was no significantly different between the assay and control cells when DIDS was used in wound healing assay (F=4.61,P>0.05). Conclusions: Our study shows that abnormal expression of ANO1 correlated with the occurrence and metastasis of OSCC in clinical specimens and that silencing ANO1 greatly reduced migration ability of scc-25 cells. Calcium activated chloride channel activity of ANO1 promoted the cell migration. Thus, ANO1 could represent a new diagnostic biomarker and a potentially important therapeutic target of OSCC. Key words:Oral squamous cell carcinoma, chloride channel, metastasis.

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Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases

Cited by 17 publications

References 27 publications

Crosstalk between gut microbiota and Sirtuin-3 in colonic inflammation and tumorigenesis

Crosstalk between gut microbiota and Sirtuin-3 in colonic inflammation and tumorigenesis

The a3 Isoform Vacuolar Type H+-ATPase Promotes Distant Metastasis in the Mouse B16 Melanoma Cells

ANO1 as a marker of oral squamous cell carcinoma and silencing ANO1 suppresses migration of human scc-25 cells

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