Abstract
Heme oxygenase 1 (Hmox1) plays an important role in the growth and spread of tumor, and its expression is regulated positively by Nrf2 [nuclear factor (erythroid-derived 2)-like 2; NFE2L2] and negatively by kelch-like ECH-associated protein 1 (Keap1) and by BTB and CNC homology 1 (Bach1). Both Hmox1 and Nrf2 contribute to distant metastasis of cancer. The mRNA levels of Hmox1, Nrf2, Keap1, and Bach1 in the tumor and normal tissues of 84 subjects with colorectal cancer (CRC) were determined by real-time polymerase chain reaction. The tumor had lower Hmox1 but higher Bach1 mRNA levels than the normal tissue. The correlations of Hmox1 with components of the Nrf2 pathway were not significant in the tumor tissue of CRC subjects with distant metastasis. The ratio of Hmox1/Nrf2 mRNA level (by percentage) in the tumor tissue was lower in the subjects with distant metastasis (97.4% (84.4–111.1%)) than in those without (101.0% (92.7–136.5%)) and was a predictor for distant metastasis in CRC (odds ratio: 0.83; 95% confidence interval: 0.68–0.97) along with serum carcinoembryonic antigen (1.0027, 1.006–1.064). The mRNA level of Hmox1 in the tumor tissue of CRC is not correlated with that of the Nrf2 pathway molecules, and its ratio to the Nrf2 level may be useful for suggesting distant metastasis in CRC.
Highlights
Oxidative stress is an essential factor in the pathogenesis of gastrointestinal mucosal disease, including cancers [1], and may contribute to neoplastic transformation in colorectal cancer (CRC) through direct epithelial damage and genetic/ epigenetic alterations [2]
Nrf2 competes with BTB and cap ‘n’ collar” (CNC) homology 1 (Bach1) for binding small Maf proteins to form a heterodimer serving as a transcriptional activator that recognizes the antioxidant response element (ARE) in the promoters of Nrf2 itself, kelch-like ECHassociated protein 1 (Keap1), Bach1, and many phase II detoxifying enzymes like Heme oxygenase 1 (Hmox1) [7]
This study determined the mRNA levels of Nrf2, Keap1, Bach1, and Hmox1, both in the tumor and in normal tissues, to investigate their correlations in CRC
Summary
Oxidative stress is an essential factor in the pathogenesis of gastrointestinal mucosal disease, including cancers [1], and may contribute to neoplastic transformation in colorectal cancer (CRC) through direct epithelial damage and genetic/ epigenetic alterations [2]. Hmox is one of the main effectors in cell responses regulated by the Nrf2 [nuclear factor (erythroid-derived 2)like 2; NFE2L2] pathway [4], which is one of the major cellular defense mechanisms against oxidative stress [5]. Nrf is a “cap ‘n’ collar” (CNC) basic leucine zipper transcription factor associated with its negative regulator, kelch-like ECHassociated protein 1 (Keap1), in the cytoplasm of unstressed cells, but is released from it and translocated to the nucleus under oxidative stress [6]. CRC with Hmox expression has a lower rate of lymphatic tumor invasion and better survival than that without [13]. The role of Hmox and its interaction with the Nrf pathway in CRC remains uncertain. This study determined the mRNA levels of Nrf, Keap, Bach, and Hmox, both in the tumor and in normal tissues, to investigate their correlations in CRC
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