Implication of heme oxygenase-1 in the sensitivity of nasopharyngeal carcinomas to radiotherapy
0
Laboratory of Microbiology & Oncology, Faculty of Pharmaceutical Sciences, Sojo University
,
Kumamoto 860-0082
,
Japan
1
Department of Otorhinolaryngology, the first affiliated hospital of China Medical University
,
Shenyang, 110001
,
P. R. China
High expression of the inducible isoform of heme oxygenase (HO-1) is well known in various solid tumors in human and experimental animal models. To investigate the relationship between HO-1 and nasopharyngeal carcinomas, especially its involvement in the response of nasopharyngeal carcinomas to radiotherapy, thirty-two nasopharyngeal carcinomas were semi-quantitatively analyzed by RT-PCR, and the expression of HO-1 was correlated with the consequence after novel radiotherapy, which was evaluated by the reduction of tumor size. Among 32 nasopharyngeal carcinomas, HO-1 expression was found in19 samples (59.4%), in which 9 patients (47.4%) showed no response to radiotherapy. Interestingly, in 13 nasopharyngeal carcinoma patients with negative expression of HO-1, radiotherapy exhibited to be effective (9 patients, 69.2%) or responsive (3 patients, 23.1%). In this study, we first demonstrated the expression of HO-1 in nasopharyngeal carcinomas, and more important, these findings strongly suggest the potential of HO-1as a useful index in identifying patients with well response to radiotherapy, further these data indicate a new therapeutic for nasopharyngeal carcinoma by inhibiting HO-1 activity, which warrants further investigation.
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Background
Heme oxygenase (HO) catalyzes the rate-limiting step of
heme degradation, leading to formation of biliverdin,
carbon monoxide (CO), and free iron [1,2], which play
crucial roles in the adaptation to and/or defense against
oxidative stress and cellular stress. HO-1 is a member of
the hear shock protein family (HSP-32), and its
expression is triggered by diverse stress-inducing stimuli
including hypoxia [3], heavy metals [4], UV irradiation [5],
reactive oxygen species (ROS) and reactive nitrogen
species [5-7]. It is believed that induction of HO-1 protects
cells from these toxic stimuli by multiple mechanisms: (a)
decreasing the prooxidant level (heme) [8]; (b) increasing
the antioxidant level (bilirubin) [9]; (c) producing the
antiapoptotic molecule CO [10]; (d) inducing ferritin,
which removes and detoxifies free ferric ion [11]; (e)
preventing overstimulation of the immune response [12].
Indeed, inhibition of HO-1 by using specific HO
inhibitors such as zinc protoporphyrin or tin protoporphyrin
extended the pathological consequences of disorders
involving these stress-inducing stimuli: graft rejection
[13], ischemia-reperfusion injury [14], cisplatin
nephrotoxicity [15], and endotoxin-induced septic shock [12]. In
contrast, HO-1 inducers such as cobalt protoporphyrin
had beneficial effects on certain diseases [14,16].
More important, it is now well known that expression of
high levels of HO-1 occurs in various tumors [17], and
that HO-1 has an important role in rapid tumor growth
because of its antioxidative and antiapoptotic effects [17].
HO-1 was thus considered to be a key molecule for
tumors against the attack from the host and
chemotherapy and radiotherapy by protecting tumor cells from
oxidative insults. It is interesting to note that several tumors,
including renal cell carcinoma [18] and prostate tumors
[19] in human, express a high level of HO-1. However,
very little is known concerning the relationship of HO-1
expression and clinical features in nasopharyngeal
carcinomas (NPC). In this study, we have correlated HO-1
expression and the clinical status of nasopharyngeal
carcinomas, especially their response to radiotherapy, using
RT-PCR analysis.
Methods
Patients and tumors
Thirty-two patients diagnosed as NPC from the
Department of Otorhinolaryngology at the first affiliated
hospital of China Medical University in 2004 and 2005, were
selected for this study. Of the 32 patients, the male/female
ratio was 20:12 and the mean age was 58.9 years (range
3678) (Table 1). The tumor specimens were obtained by
pharyngoscopical biopsies. No treatments for the
malignant tumor were performed prior to this study. Staging of
the tumors was carried out according to the TNM
classification [20]. The TNM categories were determined by
clinical measurement and by a CT scan. The histological grade
was examined and classified according to the
International Union Against Cancer (UICC) scheme (G1, well
differentiated; G2, poorly differentiated; G3,
undifferentiated). All patients involved were subjected to
radiotherapy (60Co radiation, 3 Gy each time, one radiation every
two days, totally 3 times), one year after which the effect
of radiotherapy was evaluated by means of tumor size
using clinical measurement and CT scan.
a Positive (H + M) expression of HO-1.
b Negative (N) expression of HO-1.
c Chi square test, P < 0.01 significant.
Reverse Transcriptase-Polymerase Chain Reaction (RTPCR) Assay for Expression of HO-1 mRNA in NPC specime (...truncated)