Expression and function of heme oxygenase-1 in human gastric cancer

Abstract

Heme oxygenase-1 (HO-1) potently influences tumor growth and metastasis. To date, no study has been performed on HO-1 expression pattern and its clinicopathological significance in human gastric cancer (GC) cases. In this study, the expression of HO-1 in human GC tissues (n = 74) and matched non-tumoral adjacent parenchyma (n = 46) was investigated by immunohistochemistry. The correlation of HO-1 with the clinicopathological characteristics was analyzed. Results showed that HO-1 was expressed in 62 GC tissues from 74 cases (83.8%), which is significantly higher than non-tumoral adjacent parenchyma (20/46, 43.8%, P < 0.05). A high HO-1 expression rate showed a close association with well/moderate histological differentiation and negative lymph node metastasis (P < 0.05). The expression of matrix metallopeptidase 9 (MMP9) and vascular endothelial growth factor A (VEGF-A) as well as chemosensitivity to cisplatin of MKN-45 cell lines with genetically altered HO-1 status were then determined by realtime polymerase chain reaction and 3-(4,5 dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), respectively. Whether the induction or inhibition of HO-1 by cobalt-protoporphyrin-IX (CoPP) or zinc-protoporphyrin-IX (ZnPP) could affect the sensitivity of MKN-45 cells to cisplatin was also studied. Results showed that the expression of MMP9 and VEGF-A were up-regulated in MKN-45 cells overexpressing HO-1, and down-regulated in HO-1 interfered cells. HO-1 overexpression could lead to an increased resistance to cisplatin, whereas down-regulation of HO-1 expression by siRNA or chemical inhibition of HO-1 could lead to increased chemosensitivity to cisplatin in MKN-45 cells. HO-1 may have multiple effects on protection against carcinogenesis and progression in GC.

Upregulation of heme oxygenase-1 in colorectal cancer patients with increased circulation carbon monoxide levels, potentially affects chemotherapeutic sensitivity

“…These findings were consistent with the outcome got from a recent clinical study in gastric cancer patients to some extent, which showed a relatively high expression of HO-1 in human gastric cancer tissues (83.8%), compared to those in adjacent non-tumoral gastric tissues (43.8%) [43]. Accordingly, similar to most previous literatures as described above, upregulation of HO-1 seems to be one of typical biological features of CRC.…”

“…Similar results were also found in the recent clinical study of gastric cancers and oral squamous cell carcinomas [21,43]. These results seem to be in contrast to the common notions, namely HO-1 is widely known as a protective molecules in tumor cells against various stress (e.g., oxidative stress from infiltrated leukocytes and macrophages) to support the rapid tumor growth [17,32], thus aggressive and progressing tumors are thought to be accompanied with increased HO-1.…”

“…However there was an inclination that negative lymph node metastasis showed higher rate of HO-1 expression, though no significant difference was found (Table  2) and this tendency was not found in the intensity of HO-1 expression (Figure  3d). These findings are partly consistent to other clinical studies using different cancers, for example, Tsuji et al reported high HO-1 expression in oral squamous cell carcinomas without lymph node metastasis, and no significant correlations between HO-1 expression and tumor sizes as well as staging [21], similar findings were also reported for gastric cancers [43]. HO-1 expression in CRC may thus be helpful to indicate the risk of lymph node metastasis in CRC patients, whereas requiring further studies using large number of samples.…”

Pathological significance and prognostic implications of heme oxygenase 1 expression in non-muscle-invasive bladder cancer: Correlation with cell proliferation, angiogenesis, lymphangiogenesis and expression of VEGFs and COX-2

“…In addition to numerous physiological functions, HO-1 has important roles in various pathological conditions, including certain types of cancer. Increased expression levels of HO-1 were previously demonstrated to be associated with malignant potential, cancer cell dissemination and poor prognosis in renal cell, lung and gastric carcinomas (14,25,26). However, other studies have indicated that increased HO-1 expression levels are associated with favorable outcomes in colorectal (27) and tongue cancers (28).…”

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

“…It has important cellular functions in growth regulation and self-defense processes resisting a wide range of external stress stimuli. Overexpression of HO-1 has been found in chemoresistant myeloma ($2-fold) (Nowis et al, 2008), GC ($6-fold) (Yin et al, 2012), lung cancer ($2.5-fold) (Jeon et al, 2012), myeloid leukemia (2-11-fold) (Heasman et al, 2011). Although silenced HO-1 could abrogate drug resistance developed in the treatment with antitumor agents, the detailed mechanisms for HO-1-induced chemoresistance remain unclear.…”