Hepatocellular carcinoma (HCC) is generally believed to have low sensitivity to chemotherapeutic agents including oxaliplatin (OXA). Studies have demonstrated that gap junctions (GJs) composed of connexin (Cx) proteins have the potential to modulate drug chemosensitivity in multiple tumor cells. In the present study, we investigated the characteristics of Cx and GJs in HCC at both histologic and cytologic levels, and the effects of GJ and its effective components on OXA cytotoxicity in HCC cells in vitro. Immunohistochemistry was performed in 76 HCCs and 20 normal liver tissues to detect and locate the expression of Cx26, Cx32 and Cx43. At cytologic levels, the expression and localization of Cxs were evaluated by RT-PCR, western blot and immunofluorescence assay, respectively. The GJ function between adjacent cells was detected using dye transfer assay. The role of GJs in the modulation of OXA toxicity in HCC cells was explored using pharmacologic and molecular biologic methods. We found that Cx expression in HCC tissues was significantly lower than in normal liver tissues, and the 'internalization' from cell membrane to cytoplasm was remarkable. In vitro experiments revealed the presence of functional GJs in the SMMC-7721 HCC cells due to a small amount of Cx protein along the plasma membrane at cell-cell contacts. Regulation of this part of GJs positively influenced OXA cytotoxicity. Using RNA interference, only specific inhibition of Cx26 but not Cx32 or Cx43 reduced OXA cytotoxicity. Conversely, Cx26 overexpression by transfection of Cx26 plasmid DNA enhanced OXA cytotoxicity. This study demonstrated that during hepatocarcinogenesis, the reduced expression and internalization of Cx proteins impaired the GJ function, which further attenuated OXA cytotoxicity. Impaired GJ function may contribute to low intrinsic chemosensitivity of HCC cells to OXA, mediated by Cx26.

BackgroundTo investigate the relationship of KAI1/CD82, CD44, matrix metalloproteinase 7 (MMP7) and β-catenin, and examine its association with clinicopathological features, metastasis and prognosis in colorectal carcinoma (CRC).MethodsImmunohistochemical (IHC) analysis was used to detect the expression of KAI1/CD82, CD44, MMP7 and β-catenin in 174 archival surgical specimens of human CRC. Furthermore, clinicopathological features such as age, sex and so on were also collected retrospectively.ResultsCD44, MMP7 and β-catenin expression was positively associated with distant metastasis, lymph node metastasis and tumor-node-metastasis (TNM) stage. However, decreased KAI1/CD82 expression correlated significantly with distant metastasis, lymph node metastasis and TNM stage. KAI1/CD82 expression showed a negative correlation with CD44, MMP7 and β-catenin. Furthermore, β-catenin expression showed a positive correlation with CD44 and MMP7. Multivariate logistic regression analysis showed that KAI1/CD82 and β-catenin expression were significantly associated with lymph node metastasis and KAI1/CD82 was significantly associated with distant metastasis. Kaplan-Meier analysis revealed that CD44, MMP7 and β-catenin expression was negatively correlated with overall survival (OS), while KAI1/CD82 expression was positively correlated with OS. Low KAI1/CD82 expression and high expression of CD44, MMP7 and β-catenin was associated with a poor prognosis in CRC. Multivariate Cox regression analysis indicated that the expression of KAI1/CD82, MMP7 and β-catenin were independent predictors of OS in CRC.ConclusionThe expression of KAI1/CD82, CD44, MMP7 and β-catenin is related to tumor metastasis and prognosis in CRC. Combined detection of these factors may be of significant value in predicting the prognosis and metastasis in CRC patients.

No abstract

The impact of dental amalgam on the development of Parkinson’s disease (PD) is still uncertain, although a positive association between dental amalgam and PD has been found in a few case-control studies. The patients with amalgam fillings restored between 2000 and 2008 were identified by using the National Health Insurance Research Database (NHIRD) in Taiwan. The same number of patients who had no new amalgam filling restored was matched by sex, age, and treatment date. Both cohorts were followed up from the treatment date until the date of diagnosis of PD, death, or the end of the year 2008. The individuals who received amalgam fillings had a significantly higher risk of PD afterward (adjusted hazard ratio [HR]=1.583, 95% confidence interval [CI]=1.122–2.234, p=0.0089) than those who did not. In the individuals who received amalgam fillings, being diagnosed with diabetes or hyperlipidemia demonstrated a significantly lower HR of PD occurrence than in the patients without diabetes or hyperlipidemia (HR=0.449, 95% CI=0.254–0.794, p=0.0059; HR=0.445, 95% CI=0.260–0.763, p=0.0032) after adjusting for comorbidities and Charlson-Deyo Comorbidity Index (CCI) scores. Meanwhile, hypertension increased the hazard risk of PD (HR=1.645, 95% CI=1.098–2.464, p=0.0159). The patients exposed to dental amalgam fillings were 1.583 times more likely to have PD afterward compared to their non-exposed counterparts after adjusting for comorbidities and CCI scores.