Expression Dynamics of Heme Oxygenase-1 in Tumor Cells and the Host Contributes to the Progression of Tumors.

Jun Fang,Cheng Zhang,Shanghui Gao,Ryotaro Kunisaki,Shogo Sakaguchi,Jian-Rong Zhou,Naoya Honda,Rayhanul Islam,Kazumi Yokomizo

doi:10.3390/jpm11121340

Jun Fang, Cheng Zhang + Show 7 more

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https://doi.org/10.3390/jpm11121340

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Abstract

Heme oxygenase (HO-1) plays an important role in cellular protection against various stresses. The induction of HO-1 is an effective strategy for reactive oxygen species-related diseases, inflammatory diseases, as well as suppressing carcinogenesis. On the other hand, the high expression of HO-1 is now well known in many tumors. In this study, we investigated the dynamics of HO-1 expression in the host and the tumor. In the mouse sarcoma S180 solid tumor model and the rat hepatoma AH136B ascitic tumor model, HO-1 expression in the tumor, as indicated by the end product of HO-1 activation, i.e., carbon monoxide, gradually increased along with tumor growth. Over-expression of HO-1 expression in mouse colon cancer C26 tumor cells significantly promoted tumor growth as well as lung metastasis, whereas opposite results were found when the HO-1 expression was reduced in the cells. On the other hand, upregulating HO-1 levels in the host by using an HO-1 inducer protected the progression of the xenograft tumor in mice, whereas lowering HO-1 expression in the host with an HO-1 inhibitor showed accelerated tumor growth and lung metastasis after subcutaneous tumor xenograft inoculation. These findings strongly suggest that the balance of HO-1 levels in the host and the tumor cells is essential for the occurrence, progression, and prognosis of cancer. Maintenance of appropriately high HO-1 levels in the host is favorable for cancer prevention, whereas suppression of HO-1 in the tumor cells may thus become a therapeutic strategy for cancer.

Highlights

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Licensee MDPI, Basel, Switzerland.Heme oxygenase (HO) catalyzes the rate-limiting step in the degradation of heme to produce biliverdin, carbon monoxide (CO), and free iron (Fe2+ ) (Figure 1)
We further investigated the role of HO-1 in tumor growth and progression
Liu et al showed that survival in cultured vascular cells is mediated by the production of CO because the cytoprotection obtained from HO-1 is reversed by the CO scavenger, hemoglobin [27]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Licensee MDPI, Basel, Switzerland.Heme oxygenase (HO) catalyzes the rate-limiting step in the degradation of heme to produce biliverdin, carbon monoxide (CO), and free iron (Fe2+ ) (Figure 1). The constitutive isoform of HO (HO-2) is highly expressed in the testis and brain under physiological conditions [2]. HO-3 is an isoform detected in many organs, its enzyme activity is very low, and the physiological function remains unclear [4]. HO-1, an inducible isoform of HO, is found at low levels in most mammalian tissues but is highly expressed in the liver and spleen [5]. The expression of HO-1 is induced by a wide variety of stress-inducing stimuli, including heat shock [6], ultraviolet irradiation [7], hydrogen peroxide (H2 O2 ) [7], heavy metals [7,8], hypoxia [9], and nitric oxide (NO) [10,11]

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