CCNG1 oncogene: a novel biomarker for cancer therapy /gene therapy

Background: Metastatic cancer is associated with an invariably fatal outcome. However, DeltaRex-G, a tumor-targeted retrovector encoding a gene-edited dominant-negative CCNG1 inhibitor gene, has induced long term (>10 years) survival of patients with chemo-resistant metastatic pancreatic adenocarcinoma, malignant peripheral nerve sheath tumor, osteosarcoma, B-cell lymphoma, and breast carcinoma. Objective: To evaluate the level of CCNG1 expression in tumors as a potential biomarker for CCNG1 (Cyclin G1-blocking) inhibitor therapy. Methods: CCNG1 RNA expression levels that were previously measured as part of whole genome molecular profiling of tumors (TCGA, N=9161), adjacent “tissues” (TCGA, N=678) and GTEx normal tissues (N=7187) across 22 organ sites were analyzed. Differential expression of CCNG1 and Ki-67 in primary (N= 9161) vs metastatic (N= 393) tumors were also compared in primary (N=103) vs. metastatic (N=367) skin cancers (i.e., melanoma). Statistical Analysis: To detect systematically differential expression of CCNG1 and Ki-67 expression between populations (e.g. tumor vs. normal), unpaired Student's t-tests were performed. Results: Enhanced CCNG1 RNA and Cyclin G1 protein expression were noted in tumors compared to normal analogous counterparts, and CCNG1 expression correlated significantly with that of Ki-67. Moreover, CCNG1 expression tended to be higher than that of Ki-67 in metastatic vs primary tumors. Conclusions: Taken together with the emerging Cyclin G1 / Cdk / Myc / Mdm2 / p53 Axis governing Cancer Stem Cell Competence, this supportive data indicates: (1) CCNG1 expression is frequently enhanced in tumors when compared to their normal analogous counterparts, (2) CCNG1 and Ki-67 expressions are higher in metastatic vs primary tumors, (3) CCNG1 expression is significantly correlated with that of Ki-67, and (4) CCNG1 may actually be a stronger prognostic marker of stem cell competence, chemo-refractoriness, and EMT/metastasis than Ki-67. Phase 2 studies are planned to identify patients most likely to respond favorably to CCNG1 inhibitor therapy.

Silencing the Expression of Cyclin G1 Enhances the Radiosensitivity of Hepatocellular Carcinoma in vitro and in vivo by Inducing Apoptosis

Background: Radiotherapy plays an important role in the treatment of hepatocellular carcinoma (HCC). Cyclin G1 was a novel member of the cyclin family, and it is abnormally expressed in HCC. The aim of this study was to investigate the role of cyclin G1 in the radiotherapy of HCC cells. Methods: The expression of cyclin G1 was silenced by transfection of cyclin G1-siRNA into HepG2 cells, and the expression of cyclin G1 mRNA and protein was measured by qRT-PCR and western blot analysis. The proliferation was analysed by MTT assay, and the radiosensitivity of HCC cells was detected by using a colony formation assay and a xenograft tumour model. The expression of apoptosis-related proteins (Bcl-2 and Bax) was detected by western blot analysis. Results: The expression of cyclin G1 mRNA and protein in HepG2-cyclin G1-siRNA cells is significantly decreased compared with that in HepG2 cells. Silencing the expression of cyclin G1 inhibits the proliferation of HCC cells and enhances the radiosensitivity of HepG2 cells in vitro and in vivo. HepG2-cyclin G1-siRNA significantly decreases Bcl-2 expression and increases Bax expression in cells.Conclusion: Silencing the expression of cyclin G1 enhances the radiosensitivity of HCC cells in vitro and in vivo, and the mechanism is probably related to the regulation of apoptosis-related proteins.