Increased Expression of the Δ133p53ß Isoform Enhances Brain Metastasis.

The Δ133p53ß isoform is increased in many primary tumors and has many tumor-promoting properties that contribute to increased proliferation, migration and inflammation. Here we investigated whether Δ133p53ß contributed to some of the most aggressive tumors that had metastasized to the brain. Δ133p53ß mRNA expression was measured in lung, breast, melanoma, colorectal metastases and, where available, the matched primary tumor. The presence of Δ133p53ß expression was associated with the time for the primary tumor to metastasize and overall survival once the tumor was detected in the brain. Δ133p53ß was present in over 50% of lung, breast, melanoma and colorectal metastases to the brain. It was also increased in the brain metastases compared with the matched primary tumor. Brain metastases with Δ133p53ß expressed were associated with a reduced time for the primary tumor to metastasize to the brain compared with tumors with no Δ133p53ß expression. In-vitro-based analyses in Δ133p53ß-expressing cells showed increased cancer-promoting proteins on the cell surface and increased downstream p-AKT and p-MAPK signaling. Δ133p53ß-expressing cells also invaded more readily across a mock blood-brain barrier. Together these data suggested that Δ133p53ß contributes to brain metastases by making cells more likely to invade the brain.

Reduction of lithium induced interstitial fibrosis on co-administration with amiloride.

Long-term administration of lithium is associated with chronic interstitial fibrosis that is partially reduced with exposure to amiloride. We examined potential pathways of how amiloride may reduce interstitial fibrosis. Amiloride was administered to a rat model of lithium induced interstitial fibrosis over a long term (6 months), as well as for short terms of 14 and 28 days. Kidney cortical tissue was subjected to RNA sequencing and microRNA expression analysis. Gene expression changes of interest were confirmed using immunohistochemistry on kidney tissue. Pathways identified by RNA sequencing of kidney tissue were related to 'promoting inflammation' for lithium and 'reducing inflammation' for amiloride. Validation of candidate genes found amiloride reduced inflammatory components induced by lithium including NF-κB/p65Ser536 and activated pAKTSer473, and increased p53 mediated regulatory function through increased p21 in damaged tubular epithelial cells. Amiloride also reduced the amount of Notch1 positive PDGFrß pericytes and infiltrating CD3 cells in the interstitium. Thus, amiloride attenuates a multitude of pro-inflammatory components induced by lithium. This suggests amiloride could be repurposed as a possible anti-inflammatory, anti-fibrotic agent to prevent or reduce the development of chronic interstitial fibrosis.