Abstract
BackgroundHeme oxygenase-1 (HO-1) and its major product carbon monoxide (CO) are known to be involved in the development and progression of many tumors. The present study was to elucidate the expression and function of HO-1 in colorectal cancer (CRC), specially focusing on the circulation CO levels in CRC patients and the possible roles of HO-1 in chemoresistance of colon cancer cells.MethodsOne hundred and eighteen patients received resection for colorectal cancer and polyps at China Medical University Sheng Jing Hospital, were collected in this study. HO-1 expression in CRC tissues was analyzed by immnuohistochemical staining; circulation CO levels as carboxyhemoglobin (COHb) in CRC patients were analyzed by an ABL800 FLEX blood gas analyzer. HO-1 expression in murine colon cells C26 and human colon cancer cells HT29 and DLD1 under HO-1 inducer hemin and anticancer drug pirarubicin (THP) treatment was examined by RT-PCR, and the cell viability after each treatment was investigated by MTT assay. Data were analyzed by student’s t-test or one-way ANOVA followed by Bonferroni t-test or Fisher's exact test.ResultsHO-1 expression in tumor tissues of CRC (61.0%) was significantly higher than in normal colorectal tissues and polyps tissues (29.7%, P < 0.01); well-differentiated CRC seemed to express more HO-1 (81.5%) than moderately/poorly-differentiated cancers (59.5%, P < 0.05). However, the nuclear HO-1 expression is apparently higher in moderately/poorly differentiated CRC than well-differentiated CRC probably suggesting a new mechanism of function involved in HO-1 in cancer. In parallel with HO-1 expression, circulation CO levels in CRC patients also significantly accelerated. Moreover, HO-1 expression/induction also related to the chemosensitivity of colon cells; HO inhibitor zinc protoporphyrin significantly increased cytotoxicities of THP (i.e., 2.6 – 5.3 folds compared to cells without zinc protoporphyrin treatment).ConclusionsThese findings strongly suggested HO-1/COHb is a useful diagnostic and prognostic indicator for CRC, and inhibition of HO-1 may be a option to enhance the chemotherapeutic effects of conventional anticancer drugs toward CRC.
Highlights
Heme oxygenase-1 (HO-1) and its major product carbon monoxide (CO) are known to be involved in the development and progression of many tumors
We hypothesized that endogenous CO may positively reflect the HO-1 level especially in disease conditions such as cancer, serving as the major effector of HO-1 and becoming an indicator of HO-1 expression and functions. Taking into account these context, we investigated the expression and functions of HO-1 in colorectal cancer (CRC) in clinical manifestation in the present study, special attentions being paid to CO production in CRC patients by measuring the circulation carboxyhemoglobin (COHb), which is an easy and economic way to reflect the CO in circulation
Our findings provide evidence supporting the potential value of COHb examination in clinic as a convenient and easy tool for the diagnosis and prognostic evaluation of CRC, and suggesting that inhibition of HO-1 may be a option to enhance the chemotherapeutic effects of conventional anticancer drugs toward CRC
Summary
Heme oxygenase-1 (HO-1) and its major product carbon monoxide (CO) are known to be involved in the development and progression of many tumors. High expression of HO-1 was reported in many human tumors in clinic, including brain cancer [19], prostate cancer [11], renal cell carcinoma [20], oral squamous cell carcinoma [21] as well as leukemia [22]. In this context, recently more and more evidence has implicated that HO-1 potentially functions as an important factor associated with the growth and metastasis of tumors, as well as carcinogenesis [10,23,24]. The roles of HO-1 in CRC remain to be elucidated
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