Abstract
Tumorigenesis is an immortalization process in which the growth of normal cells is uncontrolled and programmed cell death is suppressed. Molecular biologic and immunologic studies have revealed that the aberrant expression of some proto-oncogenes boosts proliferation and inhibits apoptosis, which is vital for tumor development. The hypofunction of the host immune system also drives the development and metastasis of malignant tumors. Pim-3, a member of the Pim family, is aberrantly expressed in several cancers. Data suggest that Pim-3 inhibits apoptosis by phosphorylating the proapoptotic BH3-only protein Bad. Here, we constructed a dual-function small hairpin RNA (shRNA) vector containing an shRNA targeting Pim-3 and a TLR7-stimulating ssRNA. Stimulation with this bi-functional vector in vitro promoted significant apoptosis of Hepa1-6 cells by regulating the expression of apoptosis-related proteins and induced secretion of type I IFNs. Most importantly, this bi-functional vector more effectively inhibited subcutaneous Hepa1-6 cell growth than did single shRNA and ssRNA treatment in vivo. Natural killer (NK), CD4(+) T, and CD8(+) T cells and macrophages were required for effective tumor suppression, and CD4(+) T cells were shown to play a helper role in the activation of NK cells, possibly by regulating the secretion of Th1 or Th2 cytokines. This ssRNA-shRNA bi-functional vector may represent a promising approach for tumor therapy.
Highlights
Accumulated genetic and epigenetic changes that alter the proliferation and survival pathways of normal cells have resulted in cellular transformation and progressive tumor growth [1]
Pim-3 expression in human primary hepatocellular carcinoma cells was significantly higher in tumor tissues than in nontumor tissues at both the mRNA and protein levels (Supplementary Fig. S1C and S1D)
To further determine the mechanism whereby single-stranded RNA (ssRNA) recognition leads to increased Natural killer (NK) and CD4þ T-cell activation during dual vector treatment, we evaluated TLR7 and TLR8 expression in Hepa1-6 cells after dual vector transfection
Summary
Accumulated genetic and epigenetic changes that alter the proliferation and survival pathways of normal cells have resulted in cellular transformation and progressive tumor growth [1]. Evasion of apoptosis and self-sufficiency in growth signals are essential for malignant growth. The proto-oncogene family Provirus integrating site Moloney murine leukemia virus (Pim) is a highly conserved serine/threonine kinase family that has been implicated in cancer progression [2, 3]. Three Pim kinases (Pim-1, -2, and -3) have been identified. Pim-1 and Pim-2 induce cell-cycle progression in cooperation with c-Myc, acting as inhibitors of apoptosis in hematologic malignancies and some solid tumors [2, 3]. The newest member of the family, Pim-3, is aberrantly expressed in several cancers, those of endoderm-derived organs, Authors' Affiliations: 1Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan; 2Department of Pharmacy, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong; and 3Department of Microbiology and Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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