Expression of xenobiotic metabolizing genes in head and neck cancer tissues.

BACKGROUND: Xenobiotic metabolizing genes are involved in detoxification of carcinogens. Expression of these enzymes may be one of the reasons for interindividual differences in head and neck cancer risks. The aim of current study was first to evaluate the expression of CYP1A1, GSTM1, GSTT1 and GSTP1 and second to observe its relationship with stages of head and neck cancer in Pakistani population. METHODOLOGY: Fresh biopsy tissues were taken from oncology institutional hospitals. Semi quantitative reverse transcriptase polymerase chain reaction was used to investigate CYP1A1, GSTM1, GSTT1 and GSTP1 expression in 49 head and neck cancer tumor tissue and 49 normal healthy tissues. Statistical analysis was performed to explore its association with head and neck cancer risk. RESULTS: The current study revealed that the CYP1A1 mRNA expression was markedly reduced in tissues of head and neck carcinoma compared to adjacent normal tissue (OR 4.5, CI 1.5-13.4). CYP1A1 expression was downregulated in 62.5% tissues of stage 1, 72.7% tissues of stage 2, 60% tissues of stage 3 and 100% tissues of stage 4. Undetectable or partial loss of expression of GSTM1 and GSTT1 mRNA was also observed at a higher rate in head and neck cancer tissue compared to control (OR 4.5, CI 1.5- 13.4 and OR 3.2, CI 1.1- 9.6 respectively). GSTM1 and GSTT1 expression was also downregulated in stage wise pattern; stage 1 had 50% and 12.5% tissues showing down regulation of GSTM1 and GSTT1 genes respectively, both GSTM1 and GSTT1 had 55% tissues with down regulation in stage 2, similarly stage 3 had 60% tissues showing down regulation of these genes and stage 4 had 86% and 71% tumors. GSTP1 mRNA expression was significantly higher in cancer tissue as in control tissue (OR 4.2, CI 1.2- 15.3). GSTP1 over expression also revealed related to stages with 36.4%, 60% and 71% tumor of stage 2, 3 and 4 respectively. CONCLUSION: Our results revealed that CYP1A1, GSTM1 and GSTT1 are downregulated in the head and neck cancer progression while GSTP1 is upregulated. These down regulations and up regulation were more marked in advanced stages of head and neck cancer. Therefore, CYP and GST expression may be an important mechanism involved in the carcinogenesis but the underlying mechanisms leading to such regulations in expression deserve further investigations.

Genetic variation in carcinogen metabolizing genes associated with oral cancer in pakistani population.

BACKGROUND: Xenobiotics are metabolized by either phase I enzymes like CYP1A1 or phase II enzymes like GSTs. Polymorphisms in the encoding genes (CYP1A1, GSTM1, GSTT1 and GSTP1) potentially may therefore contribute towards risk association for oral cancer. METHODOLOGY: These genes were investigated via a case control study consisting of 228 oral cancer patients and 150 cancer free normal individuals as controls. DNA was extracted from WBCs for genotyping. Polymerase chain reaction-single stranded conformational polymorphism (SSCP) was used for screening CYP1A1 and GSTP1 genes mutations. Deletion of GSTM1 and GSTT1 genes were analyzed by multiplex PCR. RESULTS: Two novel mutations were found in this study in relation to oral cancer. A substitution mutation of A2842 with C resulting in missense tyrosine to serine formation along with a frameshift mutation due to insertion of thymidine at nucleotide 2842 resulting in 495 nucleotide sequence to alter was found in oral cancer patients. GSTM1 and GSTT1 deletion polymorphism was found in significantly higher number of individuals (OR=2.08, CI 1.05-4.2; OR=1.5, CI 0.9-2.4 respectively) compared to controls. 10 patients had deletion of both GSTM1 and GSTT1 genes. GSTP1 gene was also found to have novel substitution mutations of A2848 to T and G2849 to A in exon 7 resulting in leucine to leucine and alanine to threonine formation respectively. Two intronic deletions of cytosine at positions 1074 and 1466 was found in intron 3 and 4 in patients and no control had these exonic or intronic variants in GSTP1 gene. CONCLUSION: These results suggest that accumulation of genetic changes in CYP1A1, GSTM1, GSTT1 and GSTP1 genes are associated with increased risk of oral cancer.

KAI-1/CD82, the molecule and clinical implication in cancer and cancer metastasis.

CD82, also known as KAI-1, structurally belongs to tetraspanin family while categorised as metastasis suppressor gene on functional grounds. KAI1/CD82 is localized on cell membrane and form interactions with other tetraspanins, integrins and chemokines which are respectively responsible for cell migration, adhesion and signalling. In recent years apart from its significant involvement in the suppression of secondary tumours it has also been observed that KAI1/CD82 plays a vital role in virus binding and its entry inside the cell. Decreased expression of KAI1/CD82 molecule results in aggravating cancer progression. Altered expression levels of KAI1/CD82 molecule in different types of human cancer have been implicated as having prognostic value and linking to the long term survival of the patients. Increased level of KAI1/CD82 also results in the suppression of secondary tumour growth. Increased expression of this molecule results in reduced cell invasion and cell migration due to endocytosis of epidermal growth factor receptors (EGFR). Thus, KAI-1/CD82 is a pivotal molecule in the regulation of cancer cells' behaviour and has important clinical and therapeutic implications in cancer.