Effects of the Association between Nickel and Chromium Exposure and Matrix Metalloproteinases on Oral Cancer

• Main Authors: Tzu-Hsuen Yuan, 袁子軒
• Other Authors: Yaw-Huei Hwang
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/13826596451134843883

博士 === 國立臺灣大學 === 職業醫學與工業衛生研究所 === 100 === Soil metal contamination has been found over the past two decades in Chaughua County, which is located in central Taiwan. Wastewater from local metal-related industries was suspected to be the main source of soil metal pollution. Moreover, Changhua County has a high prevalence of oral cancer that could not be explained by the well-known potential risk factors of oral cancer, and some distinctive oral cancer features were observed in this area. Previous occupational and ecological studies implied that there was a possible association between metal exposure and oral cancer development. Matrix metalloproteinases (MMPs), a family of metal-dependent proteolytic enzymes, were associated with the potential invasion and metastasis of some tumors, and the gene expressions and enzyme activities of MMP-2 and MMP-9 were reported to be correlated with oral cancer development. In addition, cellular level experiments and epidemiological studies indicated that the metal exposure might increase the expression and activity of MMP-2 and MMP-9. The aim of this study was therefore to elucidate the relationship between metal exposure and oral cancer development, the correlations between metal exposure and MMP-2 and MMP-9 in oral cancer patients, and the effects of the associations between metal exposure and MMP-2 and MMP-9 on oral cancer development. A hospital-based case-control study was conducted with 101 oral cancer patients and 104 control patients without a previous history of oral cancer from Changhua Christian Hospital (CCH). Questionnaire administration and blood sample collection were implemented after the study subjects’ regular return clinic visits. A well-trained interviewer administered the questionnaire to collect study subjects’ demographic information, lifestyle information, smoking history, history of alcohol use, betel quid chewing history, environmental and occupational exposure history, and family history of cancer. Trace levels of several metals, including nickel (Ni), chromium (Cr), arsenic (As), cadmium (Cd), mercury (Hg), lead (Pb), copper (Cu), and zinc (Zn), in blood samples were determined by inductively coupled plasma mass spectrometry. The amounts of MMP-2 and MMP-9 in the plasma samples were quantified by enzyme-linked immunosorbent assays (ELISA), and the genetic polymorphisms of the MMP-2 promoter gene at -1306 C>T and the MMP-9 promoter gene at -1562 C>T were analyzed by polymerase chain reactions (PCR). The results of the first part of this study showed that the blood nickel, chromium, copper, and zinc concentrations were higher in the oral cancer cases than in the controls (all P’s < 0.01) and that the differences in concentration between the cases and controls were most significant for blood-Ni and blood-Cr levels after being stratified by participants’ residential locations and smoking, alcohol drinking, and betel quid chewing history. Additionally, oral cancer was significantly associated with betel quid chewing (OR = 1.10, 95% CI: 1.06-1.13), high levels of blood-Ni (OR = 16.2, 95% CI: 6.59-39.8), and high levels of blood-Cr (OR = 6.80, 95% CI: 2.84-16.3) after controlling for potential confounders. The results of the second part of this study indicated that only the plasma MMP-9 levels, and not MMP-2 levels, of the cases were significantly higher than those of controls (P < 0.0001) and that oral cancer was significantly associated with MMP-9 plasma levels (OR = 1.01, 95% CI: 1.00-1.02) and betel quid chewing (OR = 1.08, 95% CI: 1.05-1.11) after adjusting for the confounding factors. In addition, blood chromium level was positively correlated with plasma MMP-9 level in oral cancer patients (P < 0.05), and significant associations between blood chromium level and plasma MMP-9 level were observed in oral cancer patients after adjusting for the known risk factors for oral cancer (P < 0.05). The results of the third part of this study demonstrated that the C/C genotype frequency of MMP-2 -1306 C>T and the T allele frequency of MMP-9 -1562 C>T were higher in the oral cancer cases than in the controls (all P’s < 0.05). The plasma MMP-2 levels were modified not only by the polymorphisms of MMP-2 -1306 C>T in both the cases and controls (all P’s < 0.05) but also by the blood arsenic and mercury levels (all P’s < 0.01); the plasma MMP-9 levels were regulated not only by the polymorphisms of MMP-9 -1562 C>T in cases (P < 0.001) but also by the blood chromium and zinc levels (all P’s < 0.01). After controlling for potential risk factors, oral cancer was found to be significantly associated with betel quid chewing (OR = 18.7, 95% CI: 6.69-52.3), high levels of blood-Ni (OR = 18.8, 95% CI: 6.93-51.0), high levels of blood-Cr (OR = 7.47, 95% CI: 2.88-19.4), high levels of plasma-MMP-9 (OR = 3.35, 95% CI: 1.30-8.66), and the T allele of MMP-9 -1562 C>T (OR = 3.21, 95% CI: 1.17-8.80). In conclusion, this study provided direct epidemiological evidence that strengthens the possible association between metal exposure and oral cancer development and that underscores the importance of plasma MMP-9 levels and the T allele of MMP-9 -1562 C>T in the mechanism of oral cancer development. Moreover, the present results implied that chromium exposure, as a result of its regulation of plasma MMP-9 levels, has a possible role in the pathogenesis of oral cancer. On the whole, this study described the possible relationship between personal environmental metal exposure and MMPs levels in the development of oral cancer; these findings might warrant further study to reduce the risk of oral cancer in the future.