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KAI1/CD82 is a metastasis suppressor gene located on human chromosome 11p11.2. It is a member of the structurally distinct family of cell surface glycoprotein, transmembrane 4-protein superfamily.1 KAI1 was initially isolated as a gene that suppressed metastasis of rat prostate tumour cells.2 KAI1 is downregulated in several types of human malignancies.3–5 The purpose of this study was to investigate the expression of KAI1 in retinoblastoma and to correlate clinicopathologically.
There were 30 archival specimens of retinoblastomas from 2000 to 2002. There were 12 tumours with no invasion of choroid, or optic nerve and 18 tumours with invasion of choroid/optic nerve, and one tumour which had metastasised to the submandibular region. There were six well differentiated tumours, six moderately differentiated tumours, and 18 poorly differentiated tumours (table 1). Immunohistochemical staining was performed using a sensitive labelled streptavidin biotin (LSAB kit, Dako) on tumours using monoclonal antibodies for tetraspanin KAI1 (C33, Novacastra) and for proliferation index Ki-67 (Clone MIB-1, Dako, Denmark) after antigen retrieval.
The immunoanalysis for KAI1 was done based on the percentage of cells and the staining intensity. KAI1 was scored after analysing 15 tumour fields and on a four tiered scale: 0, negative (0%–5% positive cells); 1+, weak to moderate (6%–30%); 2+, intense (31%–50%); and 3+, very intense (>50%). Labelling index for Ki 67 positive cells was expressed by counting a minimum of 500 cells in the staining area. Tumours were divided into two groups; group I >50% of cells showing positive Ki 67 expression and group II <50% of cells showing positive for Ki 67. Data were analysed for statistical significance.
The immunohistochemical details are given in table 1. KAI1 expression was seen in the control lymphoid follicle of the tonsil (fig 1A). Intense KAI1 positivity with more than 80% positivity was seen in all 12/12 tumours with no invasion (fig 1B). Among the 18/18 tumours with invasion, KAI1 was decreased in all 18. The invading front of the tumour had less KAI1 than the tumour at the central portion. Retinoblastomas with focal and diffuse invasion of choroid had negative KAI1 immunoreactivity. Tumours with prelaminar optic nerve invasion had weak KAI1 immunoreactivity (fig 1C). Tumours at the post-laminar and surgical end of the optic nerve (inset, fig 1C) and at the metastatic site (fig 1D) had negative KAI1 immunoreactivity. Negative KAi1 reactivity was seen in 50% (9/18) of poorly differentiated retinoblastomas. Statistically significant correlation was observed between KAi1 expression and Ki 67 labelling index in the whole study group (p<0.001). No statistically significant correlation was observed between KAI1 expression and differentiation. Significant statistical correlation was observed when KAI1 expression was compared with tumour invasion (p<0.001).
Retinoblastoma joins a growing list of cancers in which downregulation of KAI1 is associated with tumour progression. In our study KAI1 was identified by the monoclonal antibody CD33.6 It was originally shown as inhibitory to syncytium formation induced by human T cell leukaemia virus type I, and this specific inhibition to syncytium formation induced by some human T cell line by this antibody was strongly associated with altered glycosylation of cell surface antigen, suggesting that the C33 antigen—that is, KAI1, might have a possible role in the cell to cell adhesion mechanism.7
Thus, KAI1 may link to the cell surface molecules, such as integrins, E-cadherin, and other TM4SF members, and loss of KAI1 function may have a significant role in the progression of retinoblastoma.7 The mechanism of KAI1 downregulation is not known. The 5’ promoter region of the gene contains a CpG island,8 raising the possibility of gene silencing by promoter methylation. Thus, biologically, our findings suggest a potential implication of KAI1 in tumour progression and these molecules may provide novel insights into tumour progression in retinoblastoma.
Financial support: Indian Council Of Medical Research, India.
Proprietary interest: The authors have no financial interest in any of the materials used in the study.