Tumor Biology

Cytochrome b5 reductase 2 (CYB5R2), a member of the flavoprotein pyridine nucleotide cytochrome reductase family, is associated with a number of physiological reactions. However, its role in cancer, especially nasopharyngeal carcinoma (NPC), has not been addressed. Here, we investigate the transcript levels and promoter methylation status of CYB5R2 in NPC derived cell lines and tumor biopsies and experimentally address its role as a tumor suppressor gene. We find that CYB5R2 transcript levels are decreased in NPC cell lines and tumor biopsies. Promoter hypermethylation of CYB5R2 was detected in all six tested NPC cell lines and in 84 % of primary NPC tumor biopsies but not in normal nasopharyngeal epithelium. Clinically, CYB5R2 methylation was associated with lymph node metastasis in NPC patients (P < 0.05). The endogenous expression of CYB5R2 could be restored in vitro by the methyltransferase inhibitor 5-aza-2′-deoxycytidine in NPC cell lines. Ectopic expression of CYB5R2 had an inhibitory effect on proliferation, clonogenicity and migration of NPC cells. Moreover, in vivo tests in nude mice indicated that ectopic expression of CYB5R2 reduces the tumorigenicity of CYB5R2-negative NPC cells. Collectively, these findings suggest that CYB5R2 may be a functional tumor suppressor gene, frequently inactivated by hypermethylation of its promoter in NPC. We report here the first instance of epigenetic downregulation in NPC tumor biopsies of a key enzyme, CYB5R2, which is responsible for the detoxification of environmental carcinogens. We propose the possibility of utilizing CYB5R2 promoter methylation as a diagnostic biomarker of NPC in the future.

The formation of blood capillaries to sustain development and growth of new tissues is referred to as angiogenesis. Angiogenesis is pivotal in both carcinogenesis and metastasis since capillaries are the sole source of supplying nutrients and oxygen to the proliferating tumor cells; therefore, this dependency of tumor growth on angiogenesis challenges researchers to halt tumor growth by targeting angiogenesis with the help of either synthetic or natural inhibitors. Many synthetic inhibitors of angiogenesis have not only come into force but also resulted in some severe adverse effects. Natural compounds may effectively fit into this condition and possibly decrease the time of treatment. In the recent past, literature is replete with evidences advocating the usefulness of natural compounds that target multiple biochemical pathways. The additional advantage of natural compounds is that their active principles interact with one another and work synergistically to give more meaningful and reliable effects than individual principle. Hence, if we are somehow able to combine more than two natural compounds, then it may be possible to enhance their potential by many folds, which shall prove to be very effective in combating tumor angiogenesis. This review shall discuss the concept of angiogenesis, molecular pathways, and angiogenic inhibitors and their specific targets and potential of natural compounds to greatly enhance the current knowledge of angiogenesis-inhibiting factors.

Although antivascular endothelial growth factor a (VEGFa) treatment has been well applied in cervical cancer therapy, the underlying molecular basis has not been precisely identified. Here, we examined the levels of VEGFa on the tumor growth and invasion in four commonly used human cervical cancer cell lines. We found that overexpression of VEGFa in these lines increased the tumor growth and invasiveness, while inhibition of VEGFa decreased the tumor growth and invasiveness. To figure out the involved signaling pathways, we applied specific inhibitors for ERK/MAPK, JNK, and PI3K/Akt signaling pathways, respectively, to VEGFa-overexpressing cervical cancer lines and found that only inhibition of PI3K/Akt signal transduction abolished VEGFa-induced increases in cell growth and invasiveness. Inhibition of Akt downstream mTor signaling similarly inhibited cell growth and invasion in VEGFa-overexpressing cervical cancer cells, suggesting that VEGFa may activate PI3K/Akt, and subsequently its downstream mTor signaling pathway, to promote cervical cancer cell growth and invasion. Furthermore, the effects of VEGFa-induced activation of mTor signaling cascades appeared to promote cancer cell growth through cyclinD1 and CDK4 activation and promote cancer cell invasion through MMP2 and MMP3. Taken together, our data suggest that anti-VEGFa treatment in cervical cancer may inhibit both tumor cell growth and invasion through PI3k/Akt/mTor signaling pathway.

Increasing scientific evidences suggest that aerobic exercise may improve cancer-related fatigue in breast cancer patients, but many existing studies have yielded inconclusive results. This meta-analysis aimed to derive a more precise estimation of the effects of aerobic exercise on cancer-related fatigue in breast cancer patients receiving chemotherapy. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched from inception through July 1, 2013 without language restrictions. Crude standardized mean difference (SMD) with 95 % confidence interval (CI) was calculated. Twelve comparative studies were assessed with a total of 1,014 breast cancer patients receiving chemotherapy, including 522 patients in the aerobic exercise group (intervention group) and 492 patients in the usual care group (control group). The meta-analysis results revealed that the Revised Piper Fatigue Scale (RPFS) scores of breast cancer patients in the intervention group were significantly lower than those in the control group (SMD = −0.82, 95% CI = −1.04 ∼ −0.60, P < 0.001). However, there was no significant difference in the Functional Assessment of Chronic Illness Treatment-Fatigue scale (FACIT-F) scores between the intervention and control groups (SMD = 0.09, 95% CI = −0.07 ∼ 0.25, P = 0.224). Subgroup analysis by ethnicity indicated that there were significant differences in RPFS and FACIT-F scores between the intervention and control groups among Asian populations (RPFS: SMD = −1.08, 95% CI = −1.35 ∼ −0.82, P < 0.001; FACIT-F: SMD = 1.20, 95 % CI = 0.70 ∼ 1.71, P < 0.001), but not among Caucasian populations (all P > 0.05). The current meta-analysis indicates that aerobic exercise may improve cancer-related fatigue in breast cancer patients receiving chemotherapy, especially among Asian populations.

We aimed to study the post-translational regulation of CD151 by the microRNA miR-152. CD151 is highly expressed in gastric cancer (GC) and has been shown to accelerate GC by enhancing invasion and metastasis; however, its regulation is still unclear. Our results showed decreased expression of miR-152 in GC tissue samples and cell lines. In addition, miR-152 complementation significantly inhibits both the proliferation and motility of GC cells. CD151 was found to be a target of miR-152, and overexpression of CD151 attenuated the suppressive effect of miR-152. Our findings highlight an essential role of miR-152 in the regulation of proliferation and motility of GC cells and suggest a potential application of miR-152 in GC treatment.

Although dendritic cells (DCs) used in DC-based immunotherapy are loaded with tumor-associated antigens, the antitumor immune response is effectively stimulated in cytotoxic specific T lymphocytes (CTLs), thereby achieving targeted killing of tumor cells without harming surrounding normal cells. This makes it a highly promising new form of therapy. In this study, we successfully created chitosan-coated EphrinA1-PE38/GM-CSF nanoparticles and transplanted them into tumor-bearing rats, resulting in the effective killing of glioma tissue and a prolonged life span. Further immunohistochemistry and flow cytometry studies revealed that the treatment was effective in increasing the number of dendritic cell activations under an immunomodulatory response. These results suggest that chitosan-coated EphrinA1-PE38/GM-CSF nanoparticles may be effective in inducing in situ activation of DCs in glioma-bearing rats, thereby generating DC vaccines in vivo.

The purpose of this study was to explore the role of miR-203 in colorectal cancer (CRC) and evaluate the correlation between miR-203 and BIRC5. The expressions of miR-203 in the tissues of 122 CRC patients (with non-tumor tissues as controls) and those from 30 healthy donors were detected by TaqMan® MicroRNA assay. BIRC5s expressions in CRC and non-tumor tissues were detected by immunohistochemistry. Significantly less miR-203 was expressed in CRC tissues (P < 0.05) than in non-tumor tissues. Furthermore, low expression level of miR-203 was correlated with distant metastasis (DM), lymph node metastasis (LNM), and TNM stage (P < 0.05), but there were no significant differences between tumor size or gender. The positive expression rates of BIRC5 in CRC and non-tumor tissues were 73.77 % (90/122) and 30.32 % (37/122), respectively. The expression intensity of BIRC5 in CRC was significantly higher than that of non-tumor tissues (P < 0.05). It was significantly correlated with DM, LNM, and TNM stage (P < 0.05). Finally, miR-203 expression was negatively associated with that of BIRC5 (r = −0.8150, P < 0.05). In conclusion, miR-203 was down-regulated in CRC tissues and involved in the onset and progression of CRC. The expressions of miR-203 and BIRC5 in CRC were significantly negatively correlated, suggesting that BIRC5 may be regulated by miR-203. miR-203 is a potential suppressor and predictive biomarker for CRC.

MicroRNAs (miRNAs) play important roles in the regulation of various tumor biological processes including proliferation and apoptosis. MiR-377 has been implicated in many types of cancer, whereas its expressional feature and potential biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we scanned the global miRNA expression profiles in PDAC from The Cancer Genome Atlas (TCGA) and found miR-377 was down-regulated significantly in PDAC. Then, its expression was measured in both pancreatic cancer tissues and cells; the data showed that miR-377 was de-regulated and inversely correlated with pathologic parameters of tumor growth or metastasis. We generated PDAC cell lines with stable overexpression or inhibition of miR-377, and our results indicated that miR-377 up-regulation significantly promoted cell viability, proliferation, and migration in PDAC cells, and also induced cell apoptosis and cell cycle arrest simultaneously. Binding-site predictions by bioinformatics showed that Pim-3 might be a potential target of miR-377. Luciferase reporter assay ulteriorly identified that miR-377 suppressed Pim-3 expression by binding the 3′-UTR. In tumor tissues, we also showed that the Pim-3 expression was inversely correlated with that of miR-377. Furthermore, stable ectopic miR-377 expression in pancreatic cancer cell lines suppressed Pim-3 expression, leading to the attenuation of Bad phosphorylation level at its Ser112 and promoting cell apoptosis. Overall, these results reveal that miR-377 may have tumor growth suppression function by down-regulating Pim-3 kinase expression to inhibit both pancreatic tumor growth and migration, and induce cell apoptosis. Hence, miR-377 may be a potential diagnostic marker and therapeutic target.

Data mining in the public domain demonstrates that cyclin-dependent kinase 4 (CDK4) is highly expressed in nasopharyngeal carcinomas (NPC). Associated with cyclin-D, CDK4 phosphorylates and inactivates retinoblastoma (Rb) protein family members and mediates progression through the G1- to the S-phase of the cell cycle. Amplification and overexpression of CDK4 has been identified in various human malignancies. However, its expression and amplification has never been systemically evaluated in NPC. This study aimed to evaluate the amplification and expression status, correlation with clinicopathological features, and prognostic implications of CDK4 based on public domain dataset and in our well-defined cohort of NPC patients. The association between CDK4 transcript level and gene dosage was explored by analysis of an independent public domain dataset. We retrospectively assessed CDK4 immunoexpression in biopsies of 124 consecutive NPC patients devoid of initial distant metastasis and treated according to consistent guidelines. The results were correlated with clinicopathological features, local recurrence-free survival (LRFS), distant metastasis-free survival (DMeFS), and disease-specific survival (DSS). High levels of CDK4 protein were positively correlated with the T 3, 4 status (p = 0.024); N 2, 3 status (p < 0.001); and the American Joint Committee on Cancer stage 3, 4 (p < 0.001). Multivariate analysis suggested high CDK4 expression was an independent prognostic indicator of worse DMeFS (p = 0.001, hazard ratio (HR) = 3.226) and DSS (p = 0.037, HR = 1.838). Although CDK4 is frequently upregulated, its gene locus is very uncommonly amplified in NPC. CDK4 overexpression is mostly independent with gene amplification and represents a potential prognostic biomarker in NPC and may indicate tumor aggressiveness through cell cycle dysregulation.