JAK/STAT signaling and cellular iron metabolism in hepatocellular carcinoma: therapeutic implications.

Iron metabolism plays a crucial role in the development and progression of hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Iron is an essential micronutrient that is involved in many physiological processes, including oxygen transport, DNA synthesis, and cellular growth and differentiation. However, excessive iron accumulation in the liver has been linked to oxidative stress, inflammation, and DNA damage, which can increase the risk of HCC. Studies have shown that iron overload is common in patients with HCC and that it is associated with a poor prognosis and reduced survival rates. Various iron metabolism-related proteins and signaling pathways such as the JAK/STAT pathway are dysregulated in HCC. Moreover, reduced hepcidin expression was reported to promote HCC in a JAK/STAT pathway-dependent manner. Therefore, it is important to understand the crosstalk between iron metabolism and the JAK/STAT pathway to prevent or treat iron overload in HCC. Iron chelators can bind to iron and remove it from the body, but its effect on JAK/STAT pathway is unclear. Also, HCC can be targeted by using the JAK/STAT pathway inhibitors, but their effect on hepatic iron metabolism is not known. In this review, for the first time, we focus on the role of the JAK/STAT signaling pathway in regulating cellular iron metabolism and its association with the development of HCC. We also discuss novel pharmacological agents and their therapeutic potential in manipulating iron metabolism and JAK/STAT signaling in HCC.

SCAMP3 promotes breast cancer progression through the c-MYC-ß-Catenin-SQSTM1 growth and stemness axis.

The cellular trafficking protein secretory-carrier-membrane-protein 3 (SCAMP3) has been previously shown to promote hepatocellular carcinoma, melanoma, glioma and pancreatic adenocarcinoma. Moreover, previous work has shown that SCAMP3 regulates the epidermal growth factor receptor (EGFR) in triple negative breast cancer (TNBC). However, the oncogenic role of SCAMP3 in different molecular subtypes of breast cancer (BRCA) remains largely unknown. In this study, the role of SCAMP3 in different molecular subtypes of BRCA was investigated using in silico, in vitro and in vivo approaches. In silico analysis of BRCA patient samples showed that SCAMP3 is highly overexpressed in different BRCA molecular subtypes, advanced disease grades and lymph node metastatic stages. Depletion of SCAMP3 inhibited BRCA cell growth, stemness, clonogenic potential and migration and promoted autophagy and cellular senescence. The expression of stemness markers CD44 and OCT4A was reduced in SCAMP3-silenced MDA-MB-231 cells. SCAMP3 overexpression promoted cell proliferation, clonogenicity, tumor spheroid formation and migration in vitro and tumor growth in vivo. SCAMP3 promoted epithelial-mesenchymal-transition (EMT) by regulating E-cadherin expression. SCAMP3 enhanced in vivo tumor growth in MDA-MB-231 tumor xenograft mouse model. Mechanistically, SCAMP3 depletion inhibited ß-Catenin, c-MYC and SQSTM1 expression, while its overexpression increased the expression of the same oncogenic proteins. Increased SCAMP3 expression associated with increased chemoresistance in BRCA cells while its depletion associated with increased sensitivity to chemotherapy. BRCA patients with high SCAMP3 expression showed poor prognosis, decreased overall survival and relapse free survival relative to counterparts with reduced SCAMP3 expression. These findings suggest that SCAMP3 exerts a wide range of oncogenic effects in different molecular subtypes of BRCA by modulating the c-MYC-ß-Catenin-SQSTM1 axis that targets tumor growth, metastasis, stemness and chemoresistance.