Interferon-induced transmembrane protein 2 is a prognostic marker in colorectal cancer and promotes its progression by activating the PI3K/AKT pathway.

BACKGROUND: Interferon-induced transmembrane protein 2 (IFITM2) is involved in repressing viral infection. This study aim to investigate the expression of IFITM2 in colorectal cancer (CRC) and explore its effect on cell proliferation, migration, and invasion. METHODS: We analyzed The Cancer Genome Atlas (TCGA) database for IFITM2 expression in colorectal cancer and used western blots to detect IFITM2 protein in specimens and cell lines of colorectal cancers. To assess the association between IFITM2 and clinical features, both univariate and multivariate cox regression analysis were conducted. Kaplan-Meier plots were used in the TCGA database to assess IFITM2 gene expression's prognostic significance. Silencing IFITM2 in SW480 and HCT116 cells was achieved by transient transfection with siRNA. Proliferation of CRCs was examined using Cell Counting Kit-8. The effect of IFITM2 on the migration and invasion of CRC cells was studied using wound healing and transwell assays. Gene set enrichment analysis (GSEA) was used to examine IFITM2-associated pathways and Western blotting was used to confirm it. RESULTS: IFITM2 was over-expressed in the CRC tissues and cells, with high IFITM2 expression related to the tumor N, M, and pathologic stages. The presence of IFITM2 significantly impacted patient survival in CRC. The proliferation of SW480 and HCT116 cells was suppressed when IFITM2 was silenced, resulting in weakened migration and invasion of CRC cells. GSEA analysis showed that IFITM2 was positively related to the phosphoinositide 3-kinase (PI3K)/AKT pathway, and western blot results confirmed that IFITM2 activated it. CONCLUSIONS: IFITM2 was over-expressed in CRC and modulated the PI3K/AKT pathway to promote CRC cells proliferation and metastasis.

Pan-cancer analysis of the oncogenic role of the core osteosarcoma gene VCAN in human tumors.

OBJECTIVE: Versican (VCAN), a member of the multifunctional glycoprotein family, is involved in various aspects of cancer progression. However, the role of VCAN in diverse cancers remains poorly defined. This research aimed to investigate the correlation between VCAN expression and the oncogenic role, as well as visualize its prognostic landscape in pan-cancer. METHODS: Raw data in regard to VCAN expression in cancer patients were acquired from GEO GeneChip public database in NCBI. Besides, we selected microarray data GSE16088 for analysis. We retrieved the genes associated with osteosarcoma (OS) from the OMIM database and identified their intersection with the core module. VCAN was suggested to be a potential marker gene for OS. Subsequently, we conducted Gene Set Enrichment Analysis (GSEA) to explore gene functional enrichment. Moreover, we performed pan-cancer analysis on VCAN to gain a comprehensive understanding of its implications across various cancer types. RESULTS: The VCAN expression in the tumor tissue was higher than that in normal tissue. Elevated expression of VCAN was associated with high the tumor stage and poor long-term survival. There was a significant positive correlation between VCAN and cancer fibroblasts in all pan cancers. Moreover, FBN1 was the intersection gene of VCAN-related genes and linker genes. ANTXR1, COL5A2, CSGALNACT2, and SPARC were the target genes of VCAN genes. GSEA analysis showed that VCAN was mainly enriched in the extracellular matrix (ECM) signaling pathway. CONCLUSION: VCAN can be used as a marker molecule for the early diagnosis of OS and holds significance as a molecule in cases of OS with distant metastasis. The ECM signaling pathway may be a core pathway in OS development and distant metastasis. These findings shed new light on therapeutics of cancers.

NUCKS1 Promotes Proliferation, Invasion and Migration of Non-Small Cell Lung Cancer by Upregulating CDK1 Expression.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a predominant type of lung cancer with a high mortality rate. OBJECTIVE: The aim of this study is to investigate the roles of nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) in NSCLC and to identify the potential mechanisms. MATERIALS AND METHODS: The expression of NUCKS1 in several NSCLC cells was detected firstly. Then, NUCKS1 was overexpressed or silenced in both A549 and NCI-H460 cells, where cell proliferation, invasion and migration were, respectively, determined, using CCK-8, colony formation assay, transwell and wound healing assays. Cell cycle analysis was performed, and the expression-associated proteins were detected by Western blotting. Subsequently, NCI-H460 cells with NUCKS1 overexpression for the subsequent tumor-bearing experiment. And the NUCKS1 expression in tumor tissues was measured by means of immunohistochemistry and Western blotting. Additionally, the STRING database predicted that Cyclin-Dependent Kinase 1 (CDK1) would bind to NUSK1, which was verified by the co-immunoprecipitation assay. Then, CDK1 was silenced by transfection with short hairpin RNA (shRNA)-CDK-1 or by exposure to CDK1 inhibitor p2767-00. And the biological characteristics of proliferation, invasion and migration were examined. RESULTS: Results indicated that NUCKS1 was overly expressed in NSCLC cells, and its overexpression promoted proliferation, invasion and migration of both A549 and NCI-H460 cells while NUCKS1 knockdown displayed the opposite effects. Moreover, the results of the xenograft experiments revealed that NUCKS1-upregulation promoted the tumor growth. Furthermore, the immunoprecipitation assay verified CDK1's interaction with NUCKS1, and CDK1 knockdown alleviates the impact of NUCKS1 overexpression on NSCLC cell proliferation, invasion and migration. CONCLUSION: Taken together, these findings demonstrated that NUCKS1 promotes proliferation, invasion and migration of NSCLC by upregulating CDK1, providing a novel putative target for the clinical treatment of NSCLC.

Allicin sensitizes hepatocellular cancer cells to anti-tumor activity of 5-fluorouracil through ROS-mediated mitochondrial pathway.

Drug resistance and hepatic dysfunction are the two major factors that limit the application of chemotherapy for hepatocellular carcinoma (HCC). It has been reported that allicin has the hepatic protective effect and antitumor activity. Hence allicin may be an ideal enhancer to chemotherapy regimen of HCC. In the present study, we demonstrated that allicin enhanced 5-fluorouracil (5-FU) inducing cytotoxicity in HCC cells. In vivo experiment, combined treatment group with allicin (5 mg/kg/d; every two days for 3 weeks) and 5-FU (20 mg/kg/d; 5 consecutive days) showed a dramatic inhibitory effect on the growth of HCC xenograft tumors in nude mice. The co-treatment group showed highly apoptotic level compared with 5-FU treated alone. Cells combined treatment with allicin and 5-FU increased intracellular reactive oxygen species (ROS) level, reduced mitochondrial membrane potential (ΔΨm), activated caspase-3 and PARP, and down-regulated Bcl-2 compared with DMSO, allicin and 5-FU treated alone. Moreover, the increase of activated caspase-3 and PARP was blocked by the ROS inhibitor antioxidant N-acetyl cysteine (NAC). In conclusion, this is the first study to demonstrate that allicin sensitized HCC cells to 5-FU induced apoptosis through ROS-mediated mitochondrial pathway. These results provided evidences for the combination used of allicin and 5-FU as a novel chemotherapy regimen in HCC.

5-Fluorouracil combined with apigenin enhances anticancer activity through mitochondrial membrane potential (ΔΨm)-mediated apoptosis in hepatocellular carcinoma.

The development of chemoresistance may reduce the efficacy of chemotherapeutic drugs for treating hepatocellular carcinoma (HCC). In the present study, the effects of apigenin on intensifying the chemosensitivity of HCC cells and an HCC xenograft model in response to 5-fluorouracil (5-FU) were investigated. Sub-toxic concentrations of apigenin (4 µmol/L) significantly enhanced the cytotoxicity of 5-FU (100 µg/mL) in HCC cells. In vivo, combined treatment with apigenin (20 mg/kg, five times/week for 3 weeks) and 5-FU (20 mg/kg for 5 consecutive days) significantly inhibited the growth of HCC xenograft tumours. Annexin V-propidium iodide dual staining assays, terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling assays and western blotting analysis were used to confirm the synergistic effects of apigenin and 5-FU on HCC apoptosis. Coincubation of HCC cells with apigenin and 5-FU increased levels of reactive oxygen species (ROS), which was followed by a decrease in the mitochondrial membrane potential (ΔΨm). In addition, combined triggered the mitochondrial apoptotic pathway, as indicated by decreased Bcl-2 expression and loss of ΔΨm, with significant activation of caspase 3 and poly(ADP-ribose) polymerase. The present study is the first to demonstrate that apigenin may potentiate the cytotoxicity of 5-FU in HCC via inhibition of ROS-mediated drug resistance and concurrent activation of the mitochondrial pathways of apoptosis.

Increased expression of OCT4 is associated with low differentiation and tumor recurrence in human hepatocellular carcinoma.

Octamer binding transcription factor 4 (OCT4), a key transcription factor required to maintain self-renewal and pluripotency of human and mouse embryonic stem cells, has been recently identified to be associated with tumorigenesis and malignant transformation of many types of cancers. This study was to determine the roles of OCT4 in HCC recurrence and their impact on the clinical outcome of HCC patients. Western blot and immunohistochemical stains were used to detect the expression of OCT4 protein in 152 HCC tissues and 40 cirrhosis tissues, as well as in 6 human HCC cell lines and normal hepatocytes. OCT4 expression in HCC cell lines and tumor tissues was higher than in normal hepatocytes and cirrhosis tissues. Overexpression of OCT4 was significantly associated with low differentiation and tumor recurrence. Patients with elevated expression of OCT4 protein usually carried a poor overall survival and high recurrence rate. Multivariate analysis showed that OCT4 expression was an independent predictive factor for HCC patients survival. OCT4 might serve as a promising biomarker for the diagnosis of highly recurrent cases of HCC and could be used as a valuable indicator for predicting the prognosis of HCC.