Elevated C1orf63 expression is correlated with CDK10 and predicts better outcome for advanced breast cancers: a retrospective study.

BACKGROUND: Chromosome 1 open reading frame 63 (C1orf63) is located on the distal short arm of chromosome 1, whose allelic loss has been observed in several human cancers. C1orf63 has been reported to be up-regulated in IL-2-starved T lymphocytes, which suggests it might be involved in cell cycle control, a common mechanism for carcinogenesis. Here we investigated the expression and clinical implication of C1orf63 in breast cancer. METHODS: Paraffin-embedded specimens, clinicopathological features and follow-up data of the breast cancer patients were collected. Publicly available microarray and RNA-seq datasets used in this study were downloaded from ArrayExpress of EBI and GEO of NCBI. KM plotter tool was also adopted. The expression of C1orf63 and CDK10, one known cell cycle-dependent tumor suppressor in breast cancer, was assessed by immunohistochemistry. Western blotting was performed to detect C1orf63 protein in human breast cancer cell lines, purchased from the Culture Collection of the Chinese Academy of Sciences, Shanghai. RESULTS: In a group of 12 human breast tumors and their matched adjacent non-cancerous tissues, C1orf63 expression was observed in 7 of the 12 breast tumors, but not in the 12 adjacent non-cancerous tissues (P < 0.001). Similar results were observed of C1orf63 mRNA expression both in breast cancer and several other cancers, including lung cancer, prostate cancer and hepatocellular carcinoma. In another group of 182 breast cancer patients, C1orf63 expression in tumors was not correlated with any clinicopathological features collected in this study. Survival analyses showed that there was no significant difference of overall survival (OS) rates between the C1orf63 (+) group and the C1orf63 (-) group (P = 0.145). However, the analyses of KM plotter displayed a valid relationship between C1orf63 and RFS (relapse free survival)/OS (P < 0.001; P = 0.007). Notablely, in breast cancers with advanced TNM stages (III ~ IV) among these 182 patients, C1orf63 expression was an independent prognostic factor predicting better clinical outcome (HR: 0.41; 95 % CI: 0.17 ~ 0.97; P = 0.042). Additionally, we found that CDK10 mRNA expression was positively correlated with C1orf63, which was consistent with the relationship of protein expression between C1orf63 and CDK10 (r s = 0.391; P < 0.001). CONCLUSIONS: Compared to adjacent non-cancerous tissues, C1orf63 expression was elevated in tumor tissues. However, C1orf63 predicts better prognosis for breast cancers with advanced TNM stage, and the underlying mechanism is unknown. In addition, C1orf63 is correlated with the cell cycle related gene, CDK10.

Lomitapide repurposing for treatment of malignancies: A promising direction.

The development of novel drugs from basic science to clinical practice requires several years, much effort, and cost. Drug repurposing can promote the utilization of clinical drugs in cancer therapy. Recent studies have shown the potential effects of lomitapide on treating malignancies, which is currently used for the treatment of familial hypercholesterolemia. We systematically review possible functions and mechanisms of lomitapide as an anti-tumor compound, regarding the aspects of apoptosis, autophagy, and metabolism of tumor cells, to support repurposing lomitapide for the clinical treatment of tumors.

SIX4, a potential therapeutic target for estrogen receptor-positive breast cancer patients, is associated with low promoter methylation level.

Aim: To investigate SIX4 in breast cancer. Methods: Publicly available online tools were used to analyze the expression, methylation and prognostic significance of SIX4 in breast cancer, as well as its immunohistochemistry. Results: High SIX4 levels were associated with low SIX4 promoter methylation, especially in estrogen receptor-positive breast cancer. Increased SIX4 was related to advanced stage and decreased immune infiltration. Gene set enrichment analysis found that the SIX4-correlated genes were enriched in transcriptional processing and immune response. Patients with high SIX4 expression tended to have poor survival, especially those with estrogen receptor-positive breast cancer. Conclusion: High SIX4 expression in breast cancer plays an oncogenic role, promoting the development of malignancies through suppressing the immune response, especially in luminal subtypes, and is associated with a low promoter methylation level.

Elevated transcriptional levels of aldolase A (ALDOA) associates with cell cycle-related genes in patients with NSCLC and several solid tumors.

BACKGROUND: Aldolase A (ALDOA) is one of the glycolytic enzymes primarily found in the developing embryo and adult muscle. Recently, a new role of ALDOA in several cancers has been proposed. However, the underlying mechanism remains obscure and inconsistent. In this study, we tried to investigate ALDOA-associated (AA) genes using available microarray datasets to help elucidating the role of ALDOA in cancer. RESULTS: In the dataset of patients with non-small-cell lung cancer (NSCLC, E-GEOD-19188), 3448 differentially expressed genes (DEGs) including ALDOA were identified, in which 710 AA genes were found to be positively associated with ALDOA. Then according to correlation coefficients between each pair of AA genes, ALDOA-associated gene co-expression network (GCN) was constructed including 182 nodes and 1619 edges. 11 clusters out of GCN were detected by ClusterOne plugin in Cytoscape, and only 3 of them have more than three nodes. These three clusters were functionally enriched. A great number of genes (43/79, 54.4%) in the biggest cluster (Cluster 1) primarily involved in biological process like cell cycle process (Pa = 6.76E-26), mitotic cell cycle (Pa = 4.09E-19), DNA repair (Pa = 1.13E-04), M phase of meiotic cell cycle (Pa = 0.006), positive regulation of ubiquitin-protein ligase activity during mitotic cell cycle (Pa = 0.014). AA genes with highest degree and betweenness were considered as hub genes of GCN, namely CDC20, MELK, PTTG1, CCNB2, CDC45, CCNB1, TK1 and PSMB2, which could distinguish cancer from normal controls with ALDOA. Their positive association with ALDOA remained after removing the effect of HK2 and PKM, the two rate limiting enzymes in glycolysis. Further, knocking down ALDOA blocked breast cancer cells in the G0/G1 phase under minimized glycolysis. All suggested that ALDOA might affect cell cycle progression independent of glycolysis. RT-qPCR detection confirmed the relationship of ALDOA with CDC45 and CCNB2 in breast tumors. High expression of the hub genes indicated poor outcome in NSCLC. ALDOA could improve their predictive power. CONCLUSIONS: ALDOA could contribute to the progress of cancer, at least partially through its association with genes relevant to cell cycle independent of glycolysis. AA genes plus ALDOA represent a potential new signature for development and prognosis in several cancers.

Quercetin promotes cell apoptosis and inhibits the expression of MMP-9 and fibronectin via the AKT and ERK signalling pathways in human glioma cells.

Gliomas are the most common and malignant primary brain tumours and are associated with a poor prognosis despite the availability of multiple therapeutic options. Quercetin, a traditional Chinese medicinal herb, is an important flavonoid and has anti-cancer activity. Here, we evaluated whether quercetin could inhibit glioma cell viability and migration and promote apoptosis. The treatment of U87-MG glioblastoma and U251 and SHG44 glioma cell lines with different concentrations of quercetin inhibited cell viability in a dose-dependent manner. Wound healing assays indicated that quercetin significantly decreased glioma cell migration. ß-galactosidase staining, DNA staining and Annexin V-EGF/PI double staining assays demonstrated that quercetin promoted cell senescence and apoptosis. In addition, the protein levels of p-AKT, p-ERK, Bcl-2, matrix metallopeptidase 9 (MMP-9) and fibronectin (FN) were significantly reduced following quercetin treatment. Therefore, we conclude that quercetin might inhibit the viability and migration and promote the senescence and apoptosis of glioma cells by suppressing the Ras/MAPK/ERK and PI3K/AKT signalling pathways. Quercetin might be a potential candidate for the clinical treatment of glioma.

Critical protein GAPDH and its regulatory mechanisms in cancer cells.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. However, emerging evidence indicates that GAPDH is implicated in diverse functions independent of its role in energy metabolism; the expression status of GAPDH is also deregulated in various cancer cells. One of the most common effects of GAPDH is its inconsistent role in the determination of cancer cell fate. Furthermore, studies have described GAPDH as a regulator of cell death; other studies have suggested that GAPDH participates in tumor progression and serves as a new therapeutic target. However, related regulatory mechanisms of its numerous cellular functions and deregulated expression levels remain unclear. GAPDH is tightly regulated at transcriptional and posttranscriptional levels, which are involved in the regulation of diverse GAPDH functions. Several cancer-related factors, such as insulin, hypoxia inducible factor-1 (HIF-1), p53, nitric oxide (NO), and acetylated histone, not only modulate GAPDH gene expression but also affect protein functions via common pathways. Moreover, posttranslational modifications (PTMs) occurring in GAPDH in cancer cells result in new activities unrelated to the original glycolytic function of GAPDH. In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized. Mechanisms and pathways involved in GAPDH regulation and its different roles in cancer cells are also described.

Phosphorylation of estrogen receptor α at serine 118 is correlated with breast cancer resistance to tamoxifen.

The aim of the present study was to explore the correlation between estrogen receptor α (ERα) phosphorylation at serines 118 and 167 and the responsiveness of patients with primary breast cancer to tamoxifen. Tumors from 104 patients with primary breast cancer who received adjuvant tamoxifen therapy at The Affiliated Cancer Hospital of Shantou University Medical College between January 2001 to December 2007 were subjected to immunohistochemical analysis with specific antibodies against ERα phosphorylated at either serine 118 (pERα-S118) and/or serine 167 (pERα-S167). ERα phosphorylation at the two sites was correlated with either the disease-free survival or the overall survival rate of these patients using the Kaplan-Meier survival analysis. pERα-S118 and pERα-S167 were found to be expressed in the cell nucleus of 25.0% (26/104) and 26.9% (28/104) of breast cancers, respectively. The expression of pERα-S118 was positively correlated with the human epidermal growth factor receptor-2 (HER-2) status (χ2=6.85, P=0.01). The Kaplan-Meier analysis revealed a poorer disease-free (P=0.022) and overall survival (P=0.013) in breast cancer patients expressing pERα-S118, but not in those expressing pERα-S167. In conclusion, pERα-S118 was correlated with the HER-2 status and predicted breast cancer resistance to tamoxifen.