|dc.description.abstract||Skin cancers are the most common cancer in human population. They are practically
divided into two major group; melanoma and non-melanoma skin cancer (NMSC).
NMSC often refers to two common neoplasms; cutaneous squamous cell carcinoma
(cSCC) and basal cell carcinoma (BCC). BCCs are slow growing, malignant,
significantly invasive but rarely metastasizing carcinomas. cSCCs are the malignant
tumor of keratinocytes with significant squamous differentiation. In contrast to
BCCs, SCCs have significant metastatic capacity. Metastasis is a complex multistep
process and strictly positively or negatively controlled by tens of genes or proteins.
Besides supporting genes, a group of gene, called metastasis suppressor genes
(MSG), slow or inhibit metastasis without significantly affecting tumorigenicity.
The aim of this study was to find out distribution and importance of the seven
selected metastasis suppressor gene/proteins including NM23-H1, NDRG1, Ecadherin,
RHOGDI2 (ARHGDIB), CD82/KAI1, MKK4, and AKAP12 in NMSC.
Ninety six BCCs, 32 cSCCs, 6 in-situ SCCs, two cell lines (HaCaT, A-431) were included
for immunohistochemistry study. Eleven BCCs, 8 normal skin adjacent to the BCCs, 3
normal skin frozen tissue, and, two cell lines were inserted for qRT-PCR studies.
Promoter methylations of CD82/KAI1 and MKK4 genes were analyzed in 7 tumors
and 5 normal tissue samples by bisulfite sequencing method.
In immunohistochemistry study, NM23-H1 was protected in NMSC. Similarly,
relatively preserved cytoplasmic expressions of NDRG1 were also detected. AKAP12
and RHOGDI2 were decreased in both tumor groups. However, CD82/KAI1
downregulation was only detected in BCCs. E-Cadherin was relatively protected in
BCCs but significant lost was seen in cSCCs. Cytoplasmic positivity of MKK4 was
more pronounced in cSCC when compared to BCCs. Immunohistochemical study of
cell lines showed similar finding as in seen cSCC. In qRT-PCR study, we found
significant upregulation of NM23-H1 (1.4 fold; p=0.032) and downregulation of
AKAP12 (-1.2 fold; p=0.006) when BCC was compared to normal skin. NDRG1
showed significantly higher levels (2.2 fold, p=0.001) in BCC when compared to the
skin adjacent to the BCC. MKK4 (-2.1-fold, P=0.001), ARHGDIB (RHOGDI2) (-4.7-fold,
P=0.001), CD82/KAI1 (-2.4-fold, P=0.001) and AKAP12 (-9.7-fold, P=0.001) were
downregulated but NDRG1 (34.4-fold, p=0.001) was upregulated in A-431 cell line
when compared to HaCaT. CD82/KAI and MKK4 promoters were heavily
unmethylated in BCCs and normal skin.
In conclusion, we have demonstrated differential expression patterns for the seven
MSPs in NMSCs. In SCCs, the MSG expression signature is similar but not identical
to BCCs. The preserved levels of NM23-H1 and NDRG1 may contribute to the nonmetastatic
features of NMSC.||en_US