Ubiquitin-like with PHD and ring-finger domain 1 (UHRF1) binds to methylated promoters of a number of tumor-suppressor genes, including p16INK4A and p14ARF, by forming complexes with DNA methyltransferases and HDAC1, resulting in the induction of carcinogenesis. Altered UHRF1 expression has been demonstrated in various types of cancers. Previous reports indicate that UHRF1 expression is regulated by E2F-1 expression. We investigated UHRF1 expression using immunohistochemical staining in 231 colorectal cancer and 40 adenoma specimens, analyzed the relationship between UHRF1 expression and clinicopathological findings and the association between UHRF1 and E2F-1 expression. To better understand the biological function of UHRF1 in colorectal cancer, knockdown of UHRF1 expression was performed using siRNA methods. High UHRF1 expression was observed in 152 of 231 (65.8%) colorectal cancer patients, and was detected in 35 of 40 adenoma specimens samples (87.5%). UHRF1 staining was detected in the nucleus of cancer cells, while it was not detected in colonic normal mucosa. High UHRF1 expression was significantly observed in right compared with left hemicolon cancer (p=0.008). Moreover, high UHRF1 expression tended to be associated with depth of invasion (p=0.051). UHRF1 expression was significantly associated with E2F-1 expression (p<0.0001). Knockdown of UHRF1 expression suppressed cellular growth in colon cancer cell lines, HCT116 and SW620. In conclusion, we demonstrated that UHRF1 expression was upregulated in approximately two-thirds of colorectal cancer specimens and was particularly expressed in right compared with left hemicolon cancer. Moreover, knockdown of UHRF1 expression induced growth inhibition in colon cancer cell lines. UHRF1 may be involved in cellular proliferation and molecular pathogenesis of colorectal cancer in the right hemicolon.
The aim of this study was to clarify the clinical implications of a unique carbohydrate determinant, MECA-79, in gastric cancer specimens and cells. Immunohistochemical analysis showed that 62 of 225 (27.6%) cases were defined as positive for MECA-79. MECA-79 expression was correlated with depth of invasion, venous invasion, TNM stage, and distant metastasis. In survival analyses, patients with MECA-79 expression had worse prognosis by the log-rank test. Multivariate analysis of the Cox proportional hazard model showed that MECA-79 expression was an independent factor of a worse cancer-specific survival. Among 11 gastric cancer cells, MECA-79 was observed in only MKN7 cells, which also expressed GlcNAc6ST-2 transcript. A knockdown of GlcNAc6ST-2 in MKN7 cells showed a markedly reduced expression of MECA-79, suggesting that GlcNAc-sulfation of MECA-79 is mainly synthesized by GlcNAc6ST-2. Furthermore, real-time RT-PCR analysis revealed that GlcNAc6ST-2 was significantly increased in cancer tissues compared with paired normal mucosa. In conclusion, the expression of MECA-79 could be a useful marker for the prognosis of gastric cancer. Our results might also provide novel perspectives on the biology of MECA-79 and GlcNAc6ST-2 in cancer progression and metastasis.
Abstract. The aim of this study was to examine the expression of CD44v6, CD54, Cdx2, CXCL5, Cyclin B1, MMP-7, nm23, RCAS1 and Survivin in primary gastric cancer and to investigate whether these molecules were useful in predicting the lymph node status. They were selected as candidates for indicators of lymph node metastasis from various kinds of cancer-associated genes reported previously. In 135 cases of radically resected primary gastric adenocarcinoma, we investigated the association between the expression of these molecules and clinocopathologic factors by immunohistochemistry. The results revealed that the expression of CD44v6 and MMP-7 were significantly associated with lymph node status. By contrast, nuclear Cdx2 expression was found to be inversely correlated with lymph node metastasis. Moreover, multivariate analysis demonstrated that CD44v6, MMP-7 and nuclear Cdx2 were independent predictors for lymph node status. In conclusion, our results suggest that positive expression of both CD44v6 and MMP-7, and negative expression of nuclear Cdx2 may serve as powerful predictors of lymph node metastasis in gastric cancer. Combined evaluation of these markers could be further useful to predict lymph node status clinically.
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