Yin Hongzhuan, Fang Jun, Liao Long, Maeda Hiroshi, Su Qi
Department of General Surgery, Sheng Jing Hospital, China Medical University, Shenyang City, Liaoning Province 110004, P, R, China.
BMC Cancer. 2014 Jun 14;14:436. doi: 10.1186/1471-2407-14-436.
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. 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.
One 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.
HO-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).
These 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.
血红素加氧酶-1（HO-1）及其主要产物一氧化碳（CO）已知参与多种肿瘤的发生和发展。本研究旨在阐明HO-1在结直肠癌（CRC）中的表达及功能，特别关注CRC患者的循环CO水平以及HO-1在结肠癌细胞化疗耐药中的可能作用。
本研究收集了在中国医科大学盛京医院接受结直肠癌和息肉切除术的118例患者。通过免疫组织化学染色分析CRC组织中HO-1的表达；使用ABL800 FLEX血气分析仪分析CRC患者中作为碳氧血红蛋白（COHb）的循环CO水平。通过RT-PCR检测HO-1诱导剂血红素和抗癌药物吡柔比星（THP）处理下小鼠结肠细胞C26以及人结肠癌细胞HT29和DLD1中HO-1的表达，并通过MTT法研究每种处理后的细胞活力。数据采用学生t检验或单因素方差分析，随后进行Bonferroni t检验或Fisher精确检验。
CRC肿瘤组织中HO-1的表达（61.0%）显著高于正常结直肠组织和息肉组织（29.7%，P < 0.01）；高分化CRC似乎比中/低分化癌表达更多的HO-1（81.5%比59.5%，P < 0.05）。然而，中/低分化CRC中HO-1的核表达明显高于高分化CRC，这可能提示HO-1在癌症中涉及一种新的功能机制。与HO-1表达平行，CRC患者的循环CO水平也显著升高。此外，HO-1的表达/诱导也与结肠细胞的化疗敏感性相关；HO抑制剂锌原卟啉显著增加了THP的细胞毒性（即与未用锌原卟啉处理细胞相比增加了2.6 - 5.3倍）。
这些发现强烈提示HO-1/COHb是CRC有用的诊断和预后指标，抑制HO-1可能是增强传统抗癌药物对CRC化疗效果的一种选择。
