Oncol Res. 17(6):273-82. 2008.
Deletion at Dickkopf (dkk)-3 locus (11p15.2) is related with lower lymph node metastasis and better prognosis in head and neck squamous cell carcinomas.
Head and neck squamous cell carcinoma (HNSCC) is a frequently occurring cancer, and despite improvement of its treatment methods, including chemotherapy, radiotherapy, and surgery, the improvement of survival remains poor. Recent advances in molecular biology of human cancer indicated various molecular abnormalities in HNSCC, including activation of oncogenes and inactivation of tumor suppressor genes (TSGs). Dickkopf (Dkk)-3 gene is known as a negative regulator of Wnt signaling and is suggested to function as TSG in several kinds of malignancies. We hypothesized that Dkk-3 might play an important role in HNSCC, too. Thus, in the current study, we analyzed allelic alteration of Dkk-3 locus (chromosome 11p15.2) by means of loss of heterozygosity (LOH) analysis. The study population consisted of 50 patients with HNSCC (mean age of 65 years old). Furthermore, we also examined the correlation between LOH findings of Dkk-3 locus with clinicopathological parameters to investigate its use as a biomarker in HNSCC. A remarkable LOH ratio (57%) was detected in the cases studied, implying that Dkk-3 is likely to be involved in HNSCC carcinogenesis. However, interestingly and in contrast to the expectations, we found that the group with LOH of Dkk-3 locus had less lymph node metastasis, and showed a favorable overall survival compared to the patients with retention of Dkk-3 area in survival analysis. These results indicate that Dkk-3 can play a role in HNSCC carcinogenesis with unknown mechanism. Moreover, allelic loss at Dkk-3 locus may also be used as a novel prognostic biomarker in HNSCC.
What to examine：Does specific cancer-associated gene exist for pathogenesis and progression of HNSCC?
Results：DKK3 locus (11p15.2) showed high loss of heterozygosity (LOH), suggesting that DKK3 might play roles in
pathogenesis of HNSCC. However, paradoxically, DKK3 LOH was correlated to low incidence of lymph nodal
metastasis and poorer survival. Further investigation is necessary to find a key to an enigma.
HNSCC is thought to be occur as the results of cummulative disorders on oncogenes/tumor suppressor genes. However, specific genes that play crucial role in HNSCC are not well known. To find out such cancer-specific genes, we performed genome wide loss of heterozygosity analyses, and as a result, we pointed several chromosomal loci which are often deleted in HNSCC, including 1p, 2q, 4q, 7q, 9p, 10q, 11p and 19p.
(1) Specifically and frequently deleted chromosomal loci in HNSCC ― LOH analysis
W found that DKK family member genes are commonly located on the frequently deleted chromosomal loci.
→ DKK1: 10q11.2, DKK2:4q25, DKK3: 11p15.3, DKK4: 8p11.2
Then we designed microsatellite
markers which covers these genes,
and performed LOH analysis.
Each locus showed frequent LOH,
and especially, DKK3 locus showed
very high LOH rate (57%).
This implied that DKK3 might be a
candidate gene that might play roles
in HNSCC carcinogenesis.
(2) Correlation between LOH status in DKK3 locus and clinicopathological parameters and survival
DKK3 is reported as a tumor suppressor which functions as negative regulator of oncogenic Wnt signaling, and its expression was
dowe-regulated or lost in many kinds of malignancies. Thus we thought firstly that DKK3 LOH status might correlate to better clinical
findings. But surprisingly, patients with LOH in DKK3 locus showed significantly lower lymph nodal metastasis and significantly shorter overall survival.
These data demonstrated that DKK3 might play roles in HNSCC pathogenesis and lymph nodal metastasis.
And this is the beginning of my long journey to clarify the role of this mysterious gene.