Schlafen 5: A new target for the treatment of pancreatic cancer

▲2021·4·24-PVcon Jiashan is about to open ▲The human Schlafen (SLFN) gene family consists of 7 members, with unique biological, structural and functional characteristics.

In recent years, more and more evidence has shown that human SLFN protein may play an important and unique function in malignant tumor cells.

For example, mutations in the SLFN14 gene can lead to hereditary thrombocytopenia with defects in platelet secretion.

In promoting glioblastoma (GBM), SLFN5 promotes the migration and invasion of tumor cells, and the increase in the expression level of this gene is related to the shortening of the overall survival of GBM patients.

In addition, patients who overexpress SLFN5 have a higher risk of gastric cancer.

Recently in Oncogene, published a study titled "Schlafen 5 as a novel therapeutic target in pancreatic ductal adenocarcinoma", reporting the potential regulatory role of SLFN5 in pancreatic ductal adenocarcinoma (PDAC).

Studies have shown that SLFN5 is highly expressed in PDAC patients.

The high expression level of SLFN5 is associated with the poor prognosis of PDAC patients, which implies that SLFN5 is involved in the pathophysiological process of PDAC, leading to poor prognosis.

In vitro experiments confirmed that the loss of SLFN5 significantly reduced the viability of pancreatic cancer cells.

E2F7 is a key regulator of cell cycle progression.
Overexpression of E2F7 was found to inhibit the expression of genes required for S phase progression, leading to cell cycle arrest in S phase, accumulation of DNA damage, and apoptosis.

This study found that SLFN5 is a brand-new cell cycle S-phase propulsion stimulator through the study of the mechanism, which can be mediated by the interaction with E2F7.

SLFN5 is a new promoter of S phase progression and helps expand the treasure trove of cell cycle inhibitors currently available.

A pancreatic cancer xenograft mouse model was used to investigate whether the decreased cell viability and the delay in S-phase progression observed in SLFN5KO cells translate into anti-tumor effects in vivo.

Studies have confirmed that in the in vivo PDAC model, the targeted deletion of SLFN5 does cause the decline of PDAC cell proliferation and inhibit the growth of PDAC tumors.

The editor concludes that this study provides evidence that SLFN5 is highly expressed in PDAC, and its expression is associated with poor clinical outcomes.

Mechanism studies have determined the mechanism by which SLFN5 inhibits the cell cycle regulator E2F7.
The deletion of SLFN5 in PDAC cells increases the binding capacity of the E2F7 promoter and inhibits the expression of pro-proliferation and S-phase related genes, which in turn leads to S-phase progression Delayed and inhibited the growth of PDAC tumors (below).

This is confirmed by in vitro and in vivo experiments.

In conclusion, this study provides evidence for the involvement of SLFN5 in the pathogenesis and pathophysiology of PDAC, and supports the possibility of developing new methods for the treatment of pancreatic cancer through SLFN5 targeting.

References 1.
Schlafen 5 as a novel therapeutic target in pancreatic ductal adenocarcinoma 2.
SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects 3.
Human SLFN5 is a transcriptional co-repressor of STAT1-mediated interferon responses and promotes the malignant phenotype in glioblastoma.
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