Measles virus (MV-Edm) has been proved to be a kind of safe and effective oncolytic virus because it can selectively kill a variety of tumor cells with no harm to normal cells [1]. At present, it has been applied in a number of clinical trials. The current research about MV-Edm is to improve the tumor lytic effect for developing excellent clinical efficacy [2]. Therefore, it is necessary to target the key molecules to promote its anti-tumor effect.
MV-Edm is an enveloped negative strand RNA virus containing six genes, which encode nucleoprotein, phosphoprotein, membrane protein, fusion protein, virulence factor, hemagglutinin, and large polymerase [3]. The replication of MV-Edm starts with the adsorption of surface H protein to the host cell membrane. After specific binding with the receptor, it fuses with the host cell membrane under the action of F protein, and then the nucleocapsid is released into the cytoplasm and the replication takes place there. MV-Edm kills the receptor cell by inducing multinucleation [4, 5]. Therefore, it is important to promote the assembly, maturation and secretion of MV-Edm to improve its oncolytic effect.
Previous studies have found that enveloped viruses usually achieve assembling and propagation depending on the vesicle transport system of host cells, and formed virus particles were secreted to infect other cells [6, 7]. Cell vesicle transport is the process of transporting biomacromolecules such as proteins, polysaccharide and polynucleotides to specific organelles via different vesicles across membrane, which is the main form of substance exchange across eukaryotic cells [8]. In the transportation process, biomacromolecules are inside the vesicles or on the membrane, which is called vesicle trafficking [9].
As the largest subfamily of Ras superfamily, Rab regulates most of the intracellular transport and plays an important role in different stages of transportation [10]. It has been studied that Rab can somehow gather specific motor molecules which are related to microtubule and actin to target membrane and regulate the transportation of molecules or vesicles related to organelle [11]. It has also been proved that a few members of Rab family are closely related to the infect process of various viruses [12]. For example, Rab1, Rab5, Rab6, Rab11, Rab27 and Rab43 are involved in the infection of Herpes simplex virus 1 [13–15]. Rab1, Rab5, Rab11, Rab27 and Rab43 are involved in the infection of Influenza A virus [16, 17]. Rab11 is also involved in the infection of Mumps Virus [18].
So far, it has been also reported that Rab proteins such as Rab9 and Rab11 are involved in infection of MV-Edm [19, 20]. Theoretical basis for research on oncolytic mechanism of MV-Edm has been built based on the research findings of combination of vesicle and membrane, across-membrane transport of proteins and cell secretion and endocytosis. New methodsare also proposed to improve the oncolytic effect.
Ostrowski M. et al. found that Rab family proteins were involved in the regulation of cell membrane lysis and fusion in tumor cells during vesicle transportation. If the expression of some proteins in Rab family was inhibited, the number of cell membrane lysis was significantly reduced, especially for Rab27a [11, 21]. Further study on the role of Rab27a in tumor cell vesicle transport revealed that Rab27a mainly promoted the fusion of vesicles and cell membrane, and activated lysosome to promote cell membrane lysis [22, 23]. Rab27a has been proved to be closely related to viral assembly and vesicle transport. Recent studies have shown that infection with HCMV increases the expression of Rab27a and gather Rab27a to the membrane structure of assembly site [24].
In this study, in order to solve the key problems of limited local replication and tumor lysis about MV-Edm, we firstly explored the effect of Rab27a-mediated vesicle transport system on the oncolytic effect of MV-Edm, and found a suitable drug to regulate the vesicle transport system of tumor cells to promote the oncolytic effect. We also found that inhibiting Rab27a also reduced the generation of syncytial body induced by MV-Edm, and oncolysis was enhanced when Rab27a was increased. These experimental results could support the new thinking of oncolytic improvement based on targeted strategy. This study would be expected to promote the standardization and industrialization of anti-tumor therapy strategy of oncolytic virus, and find a new method to optimize MV-Edm mediated oncolytic strategy in the future. It may also provide theoretical basis to clinical therapy.