microRNAs Promoting Growth of Gastric Cancer Xenografts and Correlation to Clinical Prognosis

Abstract

The annual death toll for gastric cancer is in the range of 700,000 worldwide. Even in patients with early-stage gastric cancer recurrence within five years has been observed after surgical resection and following chemotherapy with therapy-resistant features. Therefore, the identification of new targets and treatment modalities for gastric cancer is of paramount importance. In this review we focus on the role of microRNAs with documented efficacy in preclinical xenograft models with respect to growth of human gastric cancer cells. We have identified 31 miRs (-10b, -19a, -19b, -20a, -23a/b, -25, -27a-3p, -92a, -93, -100, -106a, -130a, -135a, -135b-5p, -151-5p, -187, -199-3p, -215, -221-3p, -224, -340a, -382, -421, -425, -487a, -493, -532-3p, -575, -589, -664a-3p) covering 26 different targets which promote growth of gastric cancer cells in vitro and in vivo as xenografts. Five miRs (miRs -10b, 151-5p, -187, 532-3p and -589) additionally have an impact on metastasis. Thirteen of the identified miRs (-19b, -20a/b, -25, -92a, -106a, -135a, -187, -221-3p, -340a, -421, -493, -575 and -589) have clinical impact on worse prognosis in patients.

Keywords: Apoptosis; clinical prognosis; gastric cancer xenograft models; invasion; microRNA targets and inhibitors; migration; proliferation; review.; tumor growth and metastasis.

Figure 1. Up-regulated miRs mediating efficacy in gastric cancer-related in vivo models. miRs and the corresponding targets are shown. (A): miRs targeting tumor suppressor genes. PTEN: Phosphatase and tensin homolog; RASSF8: ras association domain-containing protein 8. (B): miRs targeting transcription factors. FOXA2: Forkhead-box-protein A2; RUNX1: runt-related transcription factors 1 and 3; ZHX1: zinc fingers and homeoboxes protein 1.

Figure 2. Expression of selected miRs in stomach adenocarcinoma compared to normal tissues. Data are shown for miR-106a, miR-19b, miR-20a, miR-20b, miR-221, miR-25, miR-340, miR-421, miR-493, miR-589 and miR-92a. Data from 436 tumor samples and 41 normal stomach samples derived from The Cancer Genome Atlas are shown. miR expression was quantified by RNA sequencing and is shown as log2 of normalized read counts. The red lines indicate lower versus higher expression. Expression data are shown as box plots. The line in the medium of the box represents the median value, the rectangles show the upper and lower 25% quartiles, and 50% of all data points are included in the greater rectangle. All data points, except for the outliers are located within the upper and lower whiskers.

Figure 3. Up-regulated miRs mediating efficacy in gastric cancer-related in vivo models. (A): miRs targeting ubiquitinylation related mRNAs. FBXW7: F-box/WD repeat-containing protein 7; RNF144B: ring finger protein 144B. (B): miRs targeting transmembrane receptors. CD95: cluster of differentiation 95; FASR: FAS receptor; LIFR: leukemia inhibitory factor receptor.

Figure 4. Up-regulated miRs mediating efficacy in gastric cancer-related in vivo models targeting signaling- and apoptosis-related pathways. DAPK2: Death-associated protein kinase 2; DKK-1: dickkopf-related protein-1; E2F: transcription factor E2F; HIPK: homeobox-interacting protein kinase; MOB-1A: MOB kinase activator A; p53: protein 53; PDCD4: programmed cell death protein 4; SOCS1: suppressor of cytokinase signaling 1.

Figure 5. Up-regulated miRs mediating efficacy in gastric cancer-related in vivo models. (A): miRs targeting cell-cycle-related proteins. BTG2: BTG family member 2; CCNG2: cyclin-G2. (B): miRs interfering with other targets. CMTM3: CKLF like MARVEL transmembrane domain containing 3; CRMP1: collapsin response mediator protein 1, CSMD1: CUB and sushi multiple domains 1; KDM2B: Lysine (K)-specific demethylase 2B; TIA-1: T cell intracellular antigen-1.