A major pharmacological barrier to peptide therapeutics is their susceptibility to proteolytic degradation and poor membrane permeability, which, in principle, can be overcome by nanoparticle-based delivery technologies. Proteins, by definition, are nano materials and have been clinically proven as an efficient delivery vehicle for small molecule drugs. Here we describe the design of a protein-based peptide drug carrier derived from the tetramerization domain of the chimeric oncogenic protein Bcr/Abl of chronic myeloid leukemia. A dodecameric peptide inhibitor of the p53-MDM2/MDMX interaction, termed PMI, was grafted to the N-terminal helical region of Bcr/Abl tetramer. To antagonize intracellular MDM2/MDMX for p53 activation, we extended this protein, PMI Bcr/Abl, by a C-terminal Arg-repeating hexapeptide to facilitate its cellular uptake. The resultant tetrameric protein PMI Bcr/Abl-R6 adopted an alpha-helical conformation in solution and bound to MDM2 at an affinity of 32 nM. PMI Bcr/Abl-R6 effectively induced apoptosis of HCT116 p53 +/+ cells in vitro in a p53-dependent manner and potently inhibited tumor growth in a nude mouse xenograft model by stabilizing p53 in vivo. Our proteinbased delivery strategy thus provides a clinically viable solution to p53-inspired anticancer therapy *

The Bcr/Abl plays a central role in Philadelphia chromosome‐positive (Ph+) leukemia because of the constitutively activated Abl tyrosine kinase and its downstream pathways. Currently, the clinical treatment of imatinib‐resistant patients with tyrosine kinase inhibitors is severely limited by drug resistance and adverse effects. Herein, a dual‐targeting proteolysis‐targeting chimera (PROTAC) protein drug, termed PMIBcr/Abl‐R6, is designed by engrafting an MDM2/p53 inhibition peptide sequence onto the Bcr/Abl tetramerization domain. PMIBcr/Abl‐R6, harboring a Bcr/Abl targeting sequence and an MDM2 binding sequence, acts as a PROTAC drug in Ph+ leukemia cells. Its dual‐targeting constitution suggests that PMIBcr/Abl‐R6 designs to target the tetramerization domain instead of the Abl kinase domain, therefore has the potential to overcome drug resistance mutations in the kinase domain. The efficient ability of PMIBcr/Abl‐R6 is demonstrated to simultaneously induce Bcr/Abl degradation and activate the p53 pathway. PMIBcr/Abl‐R6 has the potential to overcome drug resistance in Ph+ leukemias by multiple mechanisms.

Introduction: Chemotherapy resistance is the main cause of poor prognosis in patients with hepatocellular carcinoma (HCC). Therefore, it is important to understand the molecular mechanism of adriamycin (ADM) resistance in HCC. Increasing evidence indicates that circular RNAs (circRNAs) play a crucial regulatory role in different pathological processes. In the current study, we aimed to investigate the roles and the underlying molecular mechanism of circFoxo3 in ADM-resistant HCC. Materials and Methods: Twenty-five pairs of clinical tumors samples and matched normal tissues were collected from patients with HCC. Gain-and loss-function experiments were performed to investigate the role of circFoxo3 in ADM-resistant cells. Results: CircFoxo3 expression was increased in ADM-resistant HCC tissues and HCC cell lines and in metastatic tissues compared with non-metastatic tissues. CircFoxo3 knockdown reduces and circFoxo3 overexpression enhances HCC cell invasion and tumor growth. In addition, circFoxo3 interacted with miR-199a-5p and regulated miR-199a-5p expression. Furthermore, ATP Binding Cassette Subfamily C Member 1 (ABCC1) was identified as a new target of miR-199a-5p. CircFoxo3 interacted with miR-199a-5p to positively regulate ABCC1 expression, contributing to epithelial-mesenchymal transition progression. Conclusion: CircFoxo3 knockdown reduces and circFoxo3 overexpression enhances HCC cell invasion and tumor growth through regulation of miR-199a-5p/ABCC1 axis. Our findings reveal that circFoxo3 may be novel biomarkers and therapeutic target for HCC treatment.

Homeobox protein Emx2 is a transcription factor that is encoded by the EMX2 gene. In this study, using data from the Cancer Genome Atlas-Thyroid Cancer (TCGA-THCA), we aimed to examine the expression profile of EMX2 and its antisense transcript EMX2OS in papillary thyroid cancer (PTC), their prognostic value and potential regulatory networks. Results showed that in the three variants of PTC, EMX2 was significantly downregulated in classical PTC, while EMX2OS were significantly downregulated in follicular and classical PTC, compared with adjacent normal tissues. Kaplan-Meier survival curves showed that EMX2 and EMX2OS expression was not related to RFS in follicular PTC. In comparison, the high EMX2 or EMX2OS group were associated with better RFS compared with their respective low expression group in classical PTC (p = 0.007 and 0.004 respectively). Correlation analysis showed that EMX2 and EMX2OS were highly co-expressed in PTC tissues (Spearman’s r = 0.83). By performing stepwise regression, we found that EMX2OS was better than EMX2 in predicting RFS in classical PTC. Multivariate analysis confirmed that high EMX2OS expression was an independent indicator of favorable RFS in classical PTC (HR: 0.239, 95%CI: 0.100 = 0.569, p = 0.001), after adjustment of pathological stages and residual tumors. By performing in silico analysis, we found that the genes co-expressed with EMX2 or EMX2OS were highly overlapped. KEGG pathway analysis showed that these genes were enriched in the ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling, protein digestion and absorption and proteoglycans in cancer pathways, which are closely related to cancer initiation and progression. Based on the findings, we infer that decreased EMX2OS expression might be a valuable prognostic biomarker of unfavorable RFS in classical PTC.