Search

Abstract: Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has been shown to exhibit anti-angiogenic and anti-tumor effects apart from its antimalarial activity. In this study, we demonstrate that the combined treatment of cisplatin (CDDP) and DHA exerts a strong, synergistic anti-proliferative effect in human lung carcinoma cells, including A549 and A549/DDP cells, with an average combination index below 0.7. Moreover, the in vivo anti-tumor efficacy of CDDP treatment was increased by DHA. The enhanced anti-cancer activities were also accompanied by reduced tumor microvessel density, increased CDDP concentration within A549 and A549/DDP xenograft BALB/c athymic mice models and suppressed expression of the vascularization-related proteins HIF-1α and VEGF both in vivo and in vitro. Furthermore, the level of apoptosis in the tumor cells increased with the combined treatment of DHA and CDDP. Taken together, our results indicate that a combination of DHA and CDDP treatments synergistically affects tumor angiogenesis, and these results provide a clear rationale for the investigation of these drugs in future clinical trials. [Copyright &y& Elsevier]

Recent studies have revealed that tumor immunotherapy resistance is influenced by ADAR-mediated RNA editing, but its targets remain unelucidated. Our current study identified the poliovirus receptor (PVR) oncogene, which encodes an immune checkpoint in colorectal cancer (CRC), as a potential target for RNA editing. We performed transcriptome sequencing analysis and experimental validation in two Chinese CRC cohorts. PVR and ADAR expressions significantly increased in CRC tumors and showed positive correlations in both cohorts, coupled with upregulated PVR RNA editing in CRC tumors. Manipulation of ADAR expression by over-expression or knockdown substantially changed PVR expression and RNA editing in HTC116 CRC cells. Luciferase reporter and actinomycin D assays further revealed that RNA editing in PVR 3′-UTR could upregulate PVR RNA expression, probably by increasing the RNA stability. By increasing PVR expression, ADAR-mediate RNA editing might contribute to tumor- and immune-related gene functions and pathways in CRC. Moreover, a signature combining PVR RNA editing and expression showed promising predictive performance in CRC diagnosis in both Chinese CRC cohorts. Our findings thus highlight the importance of ADAR-mediated RNA editing in PVR up-regulation in CRC tumors and provide new insight into the application of PVR RNA editing as a novel diagnostic biomarker for CRC. • Immune checkpoint PVR was identified as a novel target of ADAR-mediated RNA editing in two Chinese CRC cohorts. • Elevated ADAR expression significantly upregulated PVR RNA editing and expression in CRC. • RNA editing in the PVR 3′-UTR significantly increased the RNA expression, probably by increasing RNA stability. • A signature combining PVR RNA editing and expression showed promising performance in CRC diagnosis in both Chinese cohorts. [ABSTRACT FROM AUTHOR]

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of X-linked retinitis pigmentosa (RP), in which exon open reading frame 15 (ORF15) of RPGR has been implicated to play a substantial role. We identified a novel hemizygous missense mutation E585K of RPGR from whole-exome sequencing of RP. RNA-Seq analysis and functional study were conducted to investigate the underlying pathogenic mechanism of the mutation. Our results showed that the mutation actually affected RPGR ORF15 splicing. RNA-Seq analysis of the human retina followed by validation in cells revealed a complex splicing pattern near the 3′ boundary of RPGR exon 14 in the ORF15 region, resulting from a variety of alternative splicing events (ASEs). The wildtype RPGR mini-gene expressed in human 293T cells confirmed these ASEs in vitro. In contrast, without new RNA species detected, the mutant mini-gene disrupted the splicing pattern of the ORF15 region, and caused loss of RPGR transcript heterogeneity. The RNA species derived from the mutant mini-gene were predominated by a minor out-of-frame transcript that was also observed in wildtype RPGR, resulting from an upstream alternative 5′ splice site in exon 14. Our findings therefore provide insights into the influence of RPGR exonic mutations on alternative splicing of the ORF15 region, and the underlying molecular mechanism of RP. Image 1 • A novel E585K missense mutation was identified in RPGR exon ORF15 from RP. • Retina RNA-Seq revealed a complex splicing pattern near the mutation location. • The mutant affected ORF15 splicing and caused loss of its transcript heterogeneity. • Mutant RNAs were predominated by an out-of-frame minor form observed in wildtype. [ABSTRACT FROM AUTHOR]