Retinoic acid receptor gamma is required for proliferation of pancreatic cancer cells.

Despite the expectation that retinoic acid receptor could be the potential therapeutic targets for pancreatic cancers, there has been the lack of information about the role and the impact of retinoic acid receptor gamma (RARγ, RARG) on pancreatic cancer, unlike other two RARs. Herein, we applied TCGA and GEO database to show that the expression and prognosis of RARG is closely related to pancreatic cancer, which demonstrates that RARG is commonly overexpressed in human pancreatic cancer and is an independent diagnostic marker predicting the poor prognosis of pancreatic cancer patients. In addition, we demonstrated that the reduction in the expression of RARG in human pancreatic cancer cells dramatically suppress their proliferation and tumor growth in vivo, partially attributable to the downregulation of tumor-supporting biological processes such as cell proliferation, antiapoptosis and metabolism and the decreased expression of various oncogenes like MYC and STAT3. Mechanistically, RARG binds on the promoters of MYC, STAT3, and SLC2A1 which is distinguished from well-known conventional Retinotic acid response elements (RAREs) and that the binding is likely to be responsible for the epigenetic activation in the level of chromatin, assessed by the measurement of deposition of the gene activation marker histone H3 K27 acetylation (H3K27ac) using ChIP-qPCR. In this study, we reveal that RARG plays important role in the tumorigenesis of pancreatic cancer and represents new therapeutic targets for human pancreatic cancer.

Targeted ferritin nanoparticle encapsulating CpG oligodeoxynucleotides induces tumor-associated macrophage M2 phenotype polarization into M1 phenotype and inhibits tumor growth.

Tumor-associated macrophages (TAM) are primarily of the M2 type that facilitates tumor growth, metastasis, and immunosuppression. Therefore, repolarizing the TAMs to the pro-inflammatory M1 type is a promising therapeutic strategy against cancer. Toll-like receptor (TLR) agonists like CpG oligodeoxynucleotides (CpG ODNs) can induce anti-tumor macrophages, however, their applications in vivo are limited by the lack of effective delivery approaches. Naked CpG ODNs fail to penetrate cell membranes and are easily cleared by nucleases, which can potentially trigger an inflammatory response in serum by systemic administration. Nanoparticles can deliver TLR agonists to the target TAMs following systemic administration and selectively accumulate in tumors and macrophages, and eventually trigger TLR signaling and M1 polarization. In this study, we developed a nanoparticle vector for the targeted delivery of CpG ODNs to M2 type TAMs by encapsulating the CpG ODNs inside human ferritin heavy chain (rHF) nanocages surface modified with a murine M2 macrophage-targeting peptide M2pep. These M2pep-rHF-CpG nanoparticles repolarized M2 TAMs to the M1 type and inhibited tumor growth in 4T1 tumor-bearing mice after intravenous injection. Furthermore, M2pep-rHF-CpG also reversed the phenotype of cultured human macrophages in vitro. Interestingly, the empty M2pep-rHF nanoparticles lacking CpG ODNs also exhibited anti-tumor ability. Taken together, M2pep-rHF nanoparticles offer a novel anti-cancer therapeutic strategy via targeted delivery of CpG ODNs to M2 type TAMs, and M2pep-rHF-CpG or M2pep-rHF nanoparticles may become promising medicines for tumor immunotherapy.

MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing.

The metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis in order to provide cancer cells with energy and substrates of biosynthesis. Therefore, it is important to elucidate mechanisms controlling the cancer metabolic switch. MTR4 is a RNA helicase associated with a nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrate that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and is an independent diagnostic marker predicting the poor prognosis of HCC patients. MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such as GLUT1 and PKM2. c-Myc binds to the promoter of the MTR4 gene and is important for MTR4 expression in HCC cells, indicating that MTR4 is a mediator of the functions of c-Myc in cancer metabolism. These findings reveal important roles of MTR4 in the cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.