Over-Activation of Minichromosome Maintenance Protein 10 Promotes Genomic Instability in Early Stages of Breast Cancer.

Genomic instability is considered as one of the key hallmark during cancer development and progression. Cellular mechanisms, such as DNA replication initiation, DNA damage and repair response, apoptosis etc are observed to block progression of genomic instability and thereby induce protective effects against cancer. DNA replication initiation protein MCM10 has been previously observed to have an increased expression in different cancer subtypes. However, MCM10 association with genomic instability, cancer development and its relevant mechanisms remain unknown. Here, using a breast cancer model, we observe a significant association of MCM10 with the degree of clinical aggressiveness in breast cancer patients. By overexpression of MCM10, we observed that MCM10 promotes tumorigenic properties in immortal non-tumorigenic mammary cells by increasing proliferation, shortening the cell cycle, and promoting tumorigenic characters in in-vivo mimicking conditions. Furthermore, overexpression of MCM10 is found to induce accumulation of ssDNA followed by overexpression of ssDNA binding protein RPA2. Mesenchymal markers such as up-regulation of Vimentin, transcription factor Snail and Twist2, and the down-regulation of E-cadherin were observed in MCM10 overexpression cells. Overall, the findings of this study revealed a novel mechanism by which MCM10 promotes genomic instability and breast cancer progression, and effectively differentiates the active degree of breast cancer aggressiveness. Thus, MCM10 has the potential to be a clinically useful biomarker as well as a therapeutic target for future breast cancer treatment.

Diagnostic utility of glypican-3 for hepatocellular carcinoma on liver needle biopsy.

AIMS: Glypican 3 (GPC3) is a heparan sulphate proteoglycan that shows elevated levels in the serum of patients with hepatocellular carcinoma (HCC), but not in healthy blood donors or patients with benign liver disease. This study explores the value of GPC3 expression for diagnosis of HCC by immunohistochemistry in liver needle biopsy specimens. METHODS: Archival material of liver needle biopsies from 54 patients with HCC, nine with focal nodular hyperplasia or focal liver cell dysplasia, five with cirrhosis, seven with hepatitis B or unremarkable liver tissue, seven with cholangiocarcinoma, and 30 with metastatic tumours, was retrieved for immunohistochemical staining with GPC3 antibody and appropriate positive and negative controls. RESULTS: Forty-five out of 54 cases of HCC showed positive GPC3 staining (83.4%). In contrast, all 58 non-HCC cases of liver biopsies, including focal nodular hyperplasia, focal liver cell dysplasia, cirrhosis, hepatitis B or unremarkable liver tissue, cholangiocarcinoma and metastatic tumours, were negative for GPC3. The sensitivity and specificity of GPC3 in HCCs were 83.4% and 100%, respectively. CONCLUSIONS: GPC3 is a valuable diagnostic marker for diagnosing HCC on liver needle biopsy. It can be used to distinguish HCC from other benign hepatic conditions and metastatic tumours in the liver.