High DKK1 Expression Correlated With Poor Prognosis Of Hepatocellular Carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the tencommon malignancies in the world. According to the statistical report ofThe International Agency for Research on Cancer (IARC), the annualnew cases of HCC in the globe reached 564,000, and the death reached549,000, of which more than half occured in China. HCC has alreadybecome the important risk for the people's health in China and all overthe world. Wnt signal pathway is the critical signal pathway to decide thegenesis and development of HCC. It plays important roles intransformation, growth, metastasis and apoptosis of HCC cell. DKK1 isthe important regulatory factor in Wnt signal pathway. The expression ofDKK1 in breast cancer, hepatoblastoma and non-small cell lungcarcinoma has been reported to be up-regulated.And the result of cDNAmicroarray analysis in our lab also revealed that the expression of DKK1in HCC tissue was significant higher than that in para-cancerous livertissue, and the nodular HCC showed significantly higher DKK1expression than solitary large HCC. It suggested that the change of DKK1expression might be a critical molecular mechanism in tumorigenesis anddevelopment of HCC. To investigate the expression of DKK1 gene in HCC and the correlation between DKK1 gene expression andclinicopathological features as well as prognosis of HCC is beneficial toexplore the mechanism in tumorigenesis and development of HCC and tofind the effective marker for recurrence and metastasis of HCC as well astreatment targets.AIM: To investigate the mRNA and protein expression of DKK1gene in hepatocellular carcinoma (HCC) and to evaluate the correlationbetween DKK1 gene expression and clinicopathological features as wellas prognosis of HCC. To provide the new target for diagnosis andtreatment of HCC.Method: 30 fresh HCC specimens and correspondingpara-cancerous liver tissues and 5 normal liver tissues from hemangiomaswere obtained by surgical resection in Xiangya Hospital,CSU betweenSeptember 2005 and October 2006. 120 Paraffin slides of HCC wereobtained by surgical resection in Xiangya Hospital between June 1998and May 2006. The mRNA expression level of DKK1 gene in HCCtissues, para-cancerous liver tissues and normal liver tissues wasexamined by reverse transcription-polymerase chain reaction (RT-PCR).The DKK1 protein expression level and sub-cellular location in 120 HCCslides were examined by Immunohistochemistry. We Compared thedifference of DKK1 mRNA and protein expression level among HCCtissues, para-cancerous liver tissues and normal liver tissues, as well asamong nodular HCC, solitary large HCC and small HCC.And then Investigated the correlation between the DKK1 expression andclinicopathological features of HCC,and the correlation between theDKK1 protein expression and recurrence, metastasis, post-operationsurvival time of HCC patients.Results: The result of RT-PCR showed that the mRNA expressionof DKK1 in HCC tissue were significantly higher than that inpara-cancerous liver tissue (P＜0.05),but there was no significantdifference between para-cancerous liver tissue and normal liver tissueshowed(P＞0.05).The mRNA expression of DKK1 in nodular HCC tissuewas also significantly higher than that in solitary large HCC and smallHCC (P＜0.05), but no significant difference between solitary large HCCand small HCC (P＞0.05). There was close correlation between DKK1gene expression and vein invasion (P＜0.05), but no correlation with sex,age, diameter of tumor, numbers of tumor node, cell differentiation,cirrhosis and capsule (P＞0.05).Immunohistochemistry showed that DKK1 protein was mainlyexpressed in cytoplasm. In 120 paraffin slides, the expression of DKK1 inHCC tissue was significantly higher than that in para-cancerous livertissue (P＜0.05). The expression of DKK1 protein in nodular HCC tissuewas significantly higher than that in solitary large HCC and small HCC(P＜0.05), but the difference between solitary large HCC and small HCCwas not significant (P＞0.05). The protein expression of DKK1 in nodularHCC tissue was significantly higher than that in solitary large HCC and small HCC (P＜0.05), but the difference between solitary large HCC andsmall HCC was not significant (P＞0.05). There was significantcorrelation between DKK1 protein expression and number of tumornodes,cell differentiation and tumor vein invasion (P＜0.05), but nocorrelation with sex, age, diameter of tumor, cirrhosis and capsule(P＞0.05).The survival time and tumor-free survival time of DKK1 proteinpositive expression group were significantly shorter than that of DKK1protein negative expression group.Conclusion: The mRNA and protein expression of DKK1 in HCCtissue were significantly higher than that in para-cancerous liver tissueand normal liver tissue. The mRNA and protein expression of DKK1 innodular HCC tissue were significantly higher than that in solitary largeHCC and small HCC. There was significant correlation between DKK1gene expression and the number of tumor nodes, tumor vein invasion andcell differentiation. The survival time and tumor-free survival time ofDKK1 protein positive-expression group were significantly shorter thanthat of DKK1 protein negative-expression group, suggesting a poorprognosis for the patient with high expression of DKK1. DKK1 maybecome a new diagnostic marker or treatment target for HCC.