Proliferative potential in nasopharyngeal carcinoma: correlations with metallothionein expression and tissue zinc levels

Abstract

Metallothionein (MT) is a cysteine-rich protein with pleiotropic functions and a high binding affinity for heavy metals. The present study was designed to examine the relationship between MT expression and tissue zinc levels in conjunction with cell proliferation in nasopharyngeal cancer (NPC). Proliferative activity in NPC was quantified by Ki67 immunolabelling and MT expression was determined by immunohistochemistry. Total zinc and subcellular zinc fractions were analysed by flame atomic absorption spectrometry. MT immunostaining was observed in the nuclei of NPC cells, with the percentage MT immunopositivity ranging from 3.0 to 59.7%. Thirteen tumours displayed weak MT staining and the remaining 11 showed moderate to strong immunostaining. There was a significant positive correlation between MT and Ki67 positivity (P ⍧ 0.0127). Tissue zinc levels were higher in NPC as compared with benign nasopharyngeal tissues (4.800 ⍨ 0.4610 versus 2.889 ⍨ 0.4045 µg/g dry wt tissue, respectively; P ⍧ 0.0122). Nuclear zinc levels in NPC were significantly higher than levels in membrane and cytosolic fractions (mean zinc levels 1.4840 ⍨ 0.1489, 0.6286 ⍨ 0.0789 and 0.3014 ⍨ 0.0250 µg/mg protein, respectively). A linear relationship was also observed between nuclear zinc levels and MT immunostaining (P ⍧ 0.0024) as well as with Ki67 immunopositivity (P ⍧ 0.0123). Our results show that MT and zinc are correlated with proliferative activity in NPC, providing further insights into the biology of this enigmatic and aggressive tumour.Metallothioneins (MTs) are a family of intracellular cysteinerich proteins involved in a variety of cellular processes (1-3). The pleiotropic physiological roles of MT include metalloregulatory functions in cell growth, differentiation, repair and protection against oxidative stress-induced injury and apoptosis (1,3,4). Cell proliferation is believed to be a putative function of MT as there have been reports indicating MT to be a cell cycle-dependent protein. MT-positive nuclei were observed to be present specifically in the S to G 2 M phases of the cell cycle of regenerating hepatocytes (5). A 2-to 3-fold increase in MT expression (quantitated by enzyme-linked immunosorbent Abbreviations: EGF, epidermal growth factor; MT, metallothionein; NPC, nasopharyngeal carcinoma.© Oxford University Press 1809 assay) was observed in proliferating human colonic HT-29 cells (6).The proliferative potential of MT has also been linked to zinc, a trace element which participates in the activity of a number of DNA and RNA polymerases (2,7,8). MT has a high binding affinity for zinc and Zn-MT has been hypothesized to play important roles in transmission and expression of genetic information, in response to signals for cell activation (2,8). Zinc ions are sequestered in the metal thiolate clusters of the metalloprotein (7). In this study, our aim was to investigate the relationship of MT and zinc with proliferative activity in undifferentiated nasopharyngeal carcinoma (NPC), a cancer which is common among the Chinese popul...

Significance of overexpression of metallothionein in mouse urinary bladder focal lesions induced by treatment with N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine

“…8) It contributes to metalloregulation during cell growth and differentiation. 9) High levels of MT gene expression have been detected during the late stages of gestation and in the neonatal period. 10) Enhanced synthesis of MT in rapidly proliferating tissues appears to suggest a link with cell growth.…”

Immunoexpression of Metallothionein in Oral Squamous Cell Carcinoma

“…Cancer associated fibroblasts play an important role in tumour remodelling and so MT positive fibroblasts may cause remodelling of stroma and cause tumour spread [12]. Jayasurya et al have conducted a study on expression of MT in nasopharyngeal carcinoma and its correlation with [13]. In a study conducted by Lee et al on immunoexpression of MT in areca quid chewing associated OSCC, high MT expression was associated with lymph node metastasis.…”

Analysis of Metallothionein Expression in Human Cancers.

“…Immunohistochemical detection of the MT protein has been demonstrated in colonic tumors [41], bladder cancers [3], ductal breast cancer [10, 12, 14-16, 18, 23-25, 43, 50, 55, 57], endometrial carcinoma [34], pancreatic carcinoma [42] and nasopharyngeal cancer [21,22].…”

“…MT is believed to participate in (a) cell proliferation and apoptosis [21,22,39], (b) homeostasis of zinc [8,9,54], (c) heavy metal detoxification [48], (d) resistance to anticancer drugs [31], and (e) cellular free radical scavenging [49]. In recent years, the role of MT in tumor progression has attracted a lot of attention as MT is known to influence tumor growth by affecting the fundamental cellular processes of proliferation and death.…”