Colonic expression of heme oxygenase-1 is associated with a better long-term survival in patients with colorectal cancer

Becker, Jan C.; Fukui, Hirokazu; Imai, Yasuo; Sekikawa, Akira; Kimura, Tokiko; Yamagishi, Hidetsugu; Yoshitake, Naoto; Pohle, Thorsten; Domschke, Wolfram; Fujimori, Takahiro

doi:10.1080/00365520701192383

Cited by 80 publications

(84 citation statements)

References 29 publications

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“…Induction of HO-1 by cobalt protoporphyrin or Ad-HO-1 infection inhibited the proliferation of breast carcinoma cells (16). In human colorectal and oral carcinomas, HO-1 induction may contribute to lowering the risk of lymph node metastasis (33,34). Moreover, down-regulation of HO-1 has been identified in association with increasing of malignant progression of hepatocellular carcinoma (35).…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9

Lin¹,

Shen

Hou

et al. 2008

Molecular Cancer Therapeutics

111

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In the present study, we investigated the antitumor effects of the invasiveness and migration of heme oxygenase 1 (HO-1) in human breast carcinoma cells. 12-O-tetradecanoylphorbol-13-acetate (TPA) -induced matrix metalloproteinase-9 (MMP-9) enzyme activity and gene expression at both protein and mRNA levels were examined in human breast carcinoma cells (MCF-7 and MDA-MB-231), and the addition of the MMP-9 inhibitor, SB3CT, significantly suppressed TPA-induced invasion and migration according to the in vitro Transwell assay. Elevation of HO-1 gene expression by ferric protoporphyrin IX inhibited TPA-induced invasion of MCF-7 cells, which was blocked by adding the heme oxygenase inhibitor, tin protoporphyrin IX, or transfection of cells with HO-1 short hairpin RNA. MCF-7 cells overexpressing HO-1 (MCF-7/HO-1) were established in the present study, and TPA-induced MMP-9 gene expression, tumor invasion, and colony formation were significantly reduced in MCF-7/HO-1 cells, compared with those in Neo-transfected cells. Activation of protein kinase CA/extracellular signalregulated kinases/AP-1 with stimulation of reactive oxygen species production was involved in TPA-induced invasion of MCF-7 cells, which was attenuated by HO-1 protein induced by ferric protoporphyrin IX or transfection of HO-1 expression vectors. Additionally, the addition of carbon monoxide, but not ferric ions, biliverdin, or bilirubin, inhibited TPA-induced invasion through suppressing MMP-9, extracellular signal-regulated kinases, and AP-1 activation stimulated by TPA. The beneficial role of HO-1 in blocking tumor invasion was first identified in this study.

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Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9

Lin¹,

Shen

Hou

et al. 2008

Molecular Cancer Therapeutics

111

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“…Novel therapeutic strategies for CRC are required; thus, elucidating the underlying mechanisms of 5-FU resistance is essential for the generation of novel molecular targeted therapies for overcoming drug resistance (7,11,31). There has been increasing evidence to suggest the role of epigenetic alterations in drug resistance in numerous types of cancer, such as CRC (32)(33)(34)(35); this therefore indicates that epigenetic modification may occur following the administration of 5-FU.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the occurrence of drug resistance, 5-FU was used as the standard treatment for CRC patients for several years (30,31).…”

Section: Discussionmentioning

confidence: 99%

Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells

et al. 2015

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Abstract. The mechanisms underlying drug resistance in colorectal cancer (CRC) treatment remain to be fully elucidated. Therefore, the present study aimed to investigate the underlying mechanism resistance to a widely used anticancer drug, 5-Fluorouracil (5-FU). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important transcription factor involved in cellular protection. In the present study, it was hypothesized that the epigenetic modification of Nrf2 may be a potential target for 5-FU resistance in CRC treatment. Protein and messenger RNA levels of Nrf2, heme oxygenase-1 (HO-1), DNA methylases and DNA methyltransferases were determined and DNA methylation analysis for the Nrf2 promoter was performed in a human CRC control (SNU-C5) and resistant (SNU-C5R) cell line. The results demonstrated that Nrf2 expression levels, nuclear translocation and promoter binding were significantly increased in SNU-C5R cells compared with SNU-C5 cells. Elevated levels of activated Nrf2 in SNU-C5R cells resulted in the increased protein expression and activity of HO-1. In addition, increased production of reactive oxygen species (ROS) and upregulation of ten-eleven translocation (TET)1 were observed in SNU-C5R cells compared with SNU-C5 cells. Furthermore, methylation analysis revealed Nrf2 promoter cytosine-phosphate-guanine island hypomethylation in 5-FU-treated cells. In conclusion, the results indicated that 5-FU-induced ROS production resulted in the upregulation of TET1 expression and function. In addition, these results indicated that TET-dependent demethylation of the Nrf2 promoter upregulated Nrf2 and HO-1 expression, which induced cellular protection mechanisms, ultimately leading to drug resistance.

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“…In bladder cancer, HO-1 was significantly associated with higher grade and multiple tumors (Yim et al 2011), and in lung cancer, it was demonstrated that HO-1 protein is upregulated in epithelial malignant cells in non-small cell lung cancer (NSCLC) and its expression is associated with higher stages of the disease (Degese et al 2012). Whereas in colorectal cancer, expression of HO-1 was associated with a better prognosis and longer survival time (Becker et al 2007). It is important to note that the role of HO-1 in tumor progression could be due to the effect of HO-1 on regulatory T cells (Tregs).…”

Section: Heme Oxygenase-1 and Tumor Growthmentioning

confidence: 99%

“…The number of CD4 + CD25 + regulatory T cells has been reported to increase in peripheral blood of cancer patients. These Tregs showed potent immunosuppressive activity as demonstrated by the ability to suppress the proliferation of CD4 + CD25 − T cells and inhibit NK-cell-mediated cytotoxicity (Becker et al 2007).…”

Section: Heme Oxygenase-1 and Tumor Growthmentioning

confidence: 99%

Protective role of heme oxygenase-1 in liver

2012

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Heme oxygenase-1 (HO-1) is the rate limiting enzyme in heme catabolism and degrades heme to carbon monoxide, biliverdin, and ferrous iron. HO-1 transcriptional induction occurs in response to multiple forms of chemical, physical stress and cytokines. HO-1 confers cytoprotection by inhibiting apoptosis, oxidative stress, and inflammation. Hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. It has been shown that HO-1 induction and HO-1 products interfere with replication of HCV and markedly decreased HCV replication. However, a growing body of evidence indicates that induction of HO-1 may be involved in carcinogenesis and can play a role in the metastasis and growth of tumors. The antioxidant, antiviral activity of HO-1 makes it the cytoprotective enzyme for liver tissue in HCV infection, and induction of HO-1 can be suggested as a future therapeutic approach. However, the role of HO-1 in tumor growth should not be ignored.

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Colonic expression of heme oxygenase-1 is associated with a better long-term survival in patients with colorectal cancer

Abstract: This study demonstrates that colonic HO-1 may be a prognostic marker of colorectal-cancer outcome.

Cited by 80 publications

References 29 publications

Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9

Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9

Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells

Protective role of heme oxygenase-1 in liver

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