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2.  MiR-21/miR-375 ratio is an independent prognostic factor in patients with laryngeal squamous cell carcinoma 
American Journal of Cancer Research  2015;5(5):1775-1785.
We sought to identify microRNAs that exhibit altered expression in laryngeal squamous cell carcinoma (SCC) and to determine whether microRNA expression is predictive of disease. This study was divided into three steps: (1) The expression of six miRNAs, such as up-regulated miR-223, miR-142-3p, miR-21, miR-16, miR-23a and down-regulated miR-375, was evaluated using total RNA isolated from freshly-frozen primary tumors and non-cancerous laryngeal squamous epithelial tissues and analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). (2) We also investigated the mRNA expression levels of processing elements (RNASEN, DGCR8, and DICER1) that participate in miRNA-biogenesis pathway. (3) We analyzed the relationships between the expression levels of these miRNAs and the clinicopathologic parameters of laryngeal SCC patients. In this study, we found that: (1) A marked difference in the microRNA expression pattern was observed between tumors and non-cancerous tissue. With regard to miRNA-processing elements, the expression level of RNASEN was higher in laryngeal SCC than in normal epithelium (P<0.01). (2) The miR-21/miR-375 expression ratio was highly sensitive and specific for disease prediction. Kaplan-Meier analysis revealed a significant association between high expression of miR-21/miR-375 in cancerous tissue and a worse prognosis (p=0.032). (3) Furthermore, the expression ratio of miR-21/mir-375 in patients with stage (III-IV) tumors was significantly higher than that in those with stage (I-II) tumors (p=0.006). These data suggest that the pattern of microRNA expression in primary laryngeal SCC tissues is exhibiting strong predictive potential.
PMCID: PMC4497443  PMID: 26175945
microRNA; microarray; laryngeal squamous cell carcinoma; biomarker; prognosis
3.  Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy 
American Journal of Cancer Research  2015;5(5):1580-1593.
Perillyl alcohol (POH) is a naturally occurring dietary monoterpene isolated from the essential oils of lavender, peppermint, and other plants. Medical interest in this compound was generated by research findings showing that POH was able to inhibit the growth of tumor cells in cell culture and exert cancer preventive and therapeutic activity in a variety of animal tumor models. Based on this promising preclinical work, POH was formulated in soft gelatine capsules and orally administered to cancer patients several times a day on a continuous basis. However, such clinical trials in humans yielded disappointing results, also because the large number of capsules that had to be swallowed caused hard-to-tolerate intestinal side effects, causing many patients to withdraw from treatment due to unrelenting nausea, fatigue, and vomiting. As a result, efforts to treat cancer patients with oral POH were abandoned and did not enter clinical practice. Intriguingly, clinical trials in Brazil have explored intranasal POH delivery as an alternative to circumvent the toxic limitations of oral administration. In these trials, patients with recurrent malignant gliomas were given comparatively small doses of POH via simple inhalation through the nose. Results from these studies show this type of long-term, daily chemotherapy to be well tolerated and effective. In this review, we will present the vicissitudes of POH’s evaluation as an anticancer agent, and its most recent success in therapy of patients with malignant brain tumors.
PMCID: PMC4497427  PMID: 26175929
Monoterpene; intranasal drug delivery; inhalation drug delivery; glioblastoma
4.  Polycomb protein family member CBX7 plays a critical role in cancer progression 
American Journal of Cancer Research  2015;5(5):1594-1601.
CBX7 is a polycomb protein that participates in the formation of polycomb repressive complex 1. Apart from few exceptions, CBX7 expression is lost in human malignant neoplasias and a clear correlation between its downregulated expression and a cancer aggressiveness and poor prognosis has been observed. These findings indicate a critical role of CBX7 in cancer progression. Consistently, CBX7 is able to differentially regulate crucial genes involved in cancer progression and in epithelial-mesenchymal transition, as osteopontin and E-cadherin. Recent evidences indicate a role of CBX7 also in the modulation of response to therapy. In conclusion, CBX7 represents an important prognostic factor, whose loss of expression in general indicates a bad prognosis and a progression towards a fully malignant phenotype.
PMCID: PMC4497428  PMID: 26175930
CBX7; cancer progression; polycomb group
5.  PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application 
American Journal of Cancer Research  2015;5(5):1602-1609.
Cancer stem cells (CSCs) are a subpopulation of tumor cells that possess unique self-renewal activity and mediate tumor initiation and propagation. The PI3K/Akt/mTOR signaling pathway can be considered as a master regulator for cancer. More and more recent studies have shown the links between PI3K/Akt/mTOR signaling pathway and CSC biology. Herein, we provide a comprehensive review on the role of signaling components upstream and downstream of PI3K/Akt/mTOR signaling in CSC. In addition, we also summarize various classes of small molecule inhibitors of PI3K/Akt/mTOR signaling pathway and their clinical potential in CSC. Overall, the current available data suggest that the PI3K/Akt/mTOR signaling pathway could be a promising target for development of CSC-target drugs.
PMCID: PMC4497429  PMID: 26175931
Cancer stem cells; PI3K/Akt/mTOR signaling pathway; self-renew; tumor initiation; rapamycin
6.  Glucose-6-phosphate dehydrogenase and NADPH oxidase 4 control STAT3 activity in melanoma cells through a pathway involving reactive oxygen species, c-SRC and SHP2 
American Journal of Cancer Research  2015;5(5):1610-1620.
Background: Glucose-6-phosphate dehydrogenase (G6PD) participates in glucose utilization by catalysing the first step of the pentose-phosphate pathway in mammalian cells. Previous studies have shown that changes in G6PD levels can promote tumor cell proliferation or apoptosis via the STAT3/5 pathway in a human melanoma xenograft model. G6PD cooperates with NADPH oxidase 4 (NOX4) in the cellular metabolism of reactive oxygen species (ROS) and in maintaining the intracellular redox state. Methods: In this study, the effect of G6PD or NOX4 silencing in the melanoma line A375 was examined in terms of redox state, proto-oncogene tyrosine-protein kinase Src (c-Src) and the tyrosine-specific protein phosphatase SHP2 expression as well as cell cycle progression. Results: The results demonstrate that: (1) Downregulation of cyclin D1 and CDK4 and up-regulation of p53 and p21 occurred in response to silencing of G6PD and NOX4 thus resulting in G1/S cell cycle arrest and inhibition of A375 cell proliferation. (2) The blockade of cell proliferation is primarily due to a reduced DNA-binding activity of STAT3. (3) The DNA-binding activity of STAT3 was regulated by the upstream factors, c-SRC and SHP2. Silencing of NOX4 in A375 cells inhibited c-SRC and SHP2 regulated STAT3 activity. Conclusion: The data are consistent with a novel G6PD-NOX4-NADPH-ROS-c-SRC/SHP2 pathway controlling STAT3 activity in A375 melanoma cells.
PMCID: PMC4497430  PMID: 26175932
Glucose-6-phosphate dehydrogenase; STAT3/5; NOX4; c-SRC; SHP2; cyclin D1; CDK4
7.  Quantitative DNA hypomethylation of ligand Jagged1 and receptor Notch1 signifies occurrence and progression of breast carcinoma 
American Journal of Cancer Research  2015;5(5):1621-1634.
Methylation alterations of Jagged1 and Notch1 genes have been reported in non-tumor lesions and a few cancers. However, methylation profiles of Jagged1 promoter and Notch1 exon25 in breast cancer and matched normal tissue and the association of methylation with clinicopathological characteristics still remain unclear. To explore the potential effects of aberrant DNA methylation of Jagged1 and Notch1 on occurrence and progression of breast cancer, we detected the quantitative DNA methylation of Jagged1 and Notch1 in 73 breast cancer (BC) and 20 adjacent normal breast tissues (ANBT) by using MassARRAY spectrometry. The methylation level of overall and majority individual CpG sites of the two genes were synergistically significantly lower in BC than in ANBT. The overall hypomethylation of the two genes, particularly of Jagged1 CpG_8.9.10 and Notch1 CpG_14.15.16 in primary tumors, were markedly associated with lymph node metastasis, advanced stage and high grade. The protein expressions of the both genes were examined by immunohistochemical staining in same cohorts. The expression was significantly inverse correlation with methylation. The two proteins in primary tumor were synergistically up-regulated and dramatically related to lymph node metastasis, advanced stage and high grade. Our findings suggest that the synergetic hypomethylation of Jagged1 and Notch1 genes, especially of Jagged1 CpG_8.9.10 and Notch1 CpG_14.15.16, may involve tumorigenesis and development of breast cancer. The negative relationship between methylation and expression indicates methylation role for expression regulation. The synergetic overexpression of the two proteins further indicates the effects on occurrence and progression of breast cancer.
PMCID: PMC4497431  PMID: 26175933
Jagged1; Notch1; methylation; expression; occurrence; progression; breast cancer
8.  OPCML is frequently methylated in human colorectal cancer and its restored expression reverses EMT via downregulation of smad signaling 
American Journal of Cancer Research  2015;5(5):1635-1648.
Emerging evidence has indicated that the expression of OPCML gene is frequently altered in a variety of cancers. We previously demonstrated that the OPCML gene is a target of epigenetic inactivation and its gene product exhibits tumor-suppressive properties. However, little is known regarding the effects and mechanisms of OPCML in colon cancer. We show that the loss or downregulation of OPCML is associated with its promoter hypermethylation. Methylation of the OPCML promoter was detected in all tumors and tumor-adjacent tissues, but lower methylation in normal colon tissues. The drug-induced release of epigenetic silencing was able to restore OPCML expression and the re-expression led to the suppression of cell growth. Furthermore, the increase in OPCML expression reversed a partial epithelial-to-mesenchymal (EMT)-like transition. Cell migration and invasiveness were also inhibited in response to OPCML upregulation. These actions were mediated through the inactivation of TGFβ-Smad signaling pathways. In addition, OPCML expression was associated with two upstream nuclear receptors (ERRa and RORa). Altogether, our study reveals OPCML as a potential tumor suppressor gene epigenetically silenced in colon cancer. Our study will help to elucidate the anti-invasive mechanisms of OPCML and establish new chemotherapeutic strategies for human colon cancer.
PMCID: PMC4497432  PMID: 26175934
Tumor suppressor; OPCML; methylation; cancer
9.  Effects of topoisomerase inhibitors that induce DNA damage response on glucose metabolism and PI3K/Akt/mTOR signaling in multiple myeloma cells 
American Journal of Cancer Research  2015;5(5):1649-1664.
Hallmarks of cancer cells comprise altered glucose metabolism (aerobic glycolysis) and differences in DNA damage response (DDR). Glucose transporters (GLUT), glycolytic enzymes such as hexokinase (HK) and metabolic pathways (e.g. PI3K/Akt/mTor) have been shown to be upregulated in multiple myeloma and other cancer cell lines. Here we have investigated the effects of clinically used inhibitors of topoisomerases, of DDR and of the PI3K/Akt/mTor pathway on glucose metabolism and on cell survival in multiple myeloma cells. The effects of DNA damaging topoisomerase inhibitors (doxorubicin, etoposide, topotecan), non-DNA damaging agents (bortezomib, vincristine) as well as of molecular inhibitors of DNA damage related kinases PIKKs (KU55933 [ATM], NU7026 [DNA-PKCs]) and PI3K/Akt/mTor signaling (BEZ235 [PI3K/mTor], MK-2206 [Akt]) were analyzed 24 hours after treatment of OPM-2 multiple myeloma cells. For this purpose we monitored [18F]-FDG uptake, cell viability using an ATP assay and expression of GLUT-1, hexokinase II (HKII), cleaved caspase-3 and cleaved PARP via Western-blotting. All topoisomerase inhibitors used could upregulate expression of GLUT-1 and HKII in OPM-2 cells, resulting in elevated [18F]-FDG uptake and promotion of cell survival. In contrast, bortezomib and vincristine induced a decline in [18F]-FDG uptake combined with early induction of apoptosis. Combination treatment with topoisomerase inhibitors and molecular inhibitors of PIKK and PI3K could reverse elevated [18F]-FDG uptake, as observed after application of topoisomerase inhibitors only, and aggravate induction of apoptosis. Thus, elevated glucose consumption in OPM-2 cells can be reversed by targeting both DDR and PI3K/Akt/mTOR signaling, thus providing a promising strategy in the treatment of cancer.
PMCID: PMC4497433  PMID: 26175935
Glucose metabolism; DNA damage response; topoisomerase inhibitors; apoptosis; PI3K/Akt/mTor pathway; cell survival; cancer treatment
10.  Tumor microenvironment promotes dicarboxylic acid carrier-mediated transport of succinate to fuel prostate cancer mitochondria 
American Journal of Cancer Research  2015;5(5):1665-1679.
Prostate cancer cells reprogram their metabolism, so that they support their elevated oxidative phosphorylation and promote a cancer friendly microenvironment. This work aimed to explore the mechanisms that cancer cells employ for fueling themselves with energy rich metabolites available in interstitial fluids. The mitochondria oxidative phosphorylation in metastatic prostate cancer DU145 cells and normal prostate epithelial PrEC cells were studied by high-resolution respirometry. An important finding was that prostate cancer cells at acidic pH 6.8 are capable of consuming exogenous succinate, while physiological pH 7.4 was not favorable for this process. Using specific inhibitors, it was demonstrated that succinate is transported in cancer cells by the mechanism of plasma membrane Na+-dependent dycarboxylic acid transporter NaDC3 (SLC13A3 gene). Although the level of expression of SLC13A3 was not significantly altered when maintaining cells in the medium with lower pH, the respirometric activity of cells under acidic condition was elevated in the presence of succinate. In contrast, normal prostate cells while expressing NaDC3 mRNA do not produce NaDC3 protein. The mechanism of succinate influx via NaDC3 in metastatic prostate cancer cells could yield a novel target for anti-cancer therapy and has the potential to be used for imaging-based diagnostics to detect non-glycolytic tumors.
PMCID: PMC4497434  PMID: 26175936
Prostate cancer; mitochondria oxidative phosphorylation; acidic tumor microenvironment; Na+-dicarboxylate transporter; succinate
11.  Snail interacts with Id2 in the regulation of TNF-α-induced cancer cell invasion and migration in OSCC 
American Journal of Cancer Research  2015;5(5):1680-1691.
The inflammatory tumor microenvironment has been identified to play a pivotal role in tumor development and metastasis. Tumor necrosis factor-α (TNF-α) is one of the key cytokines that regulate the inflammatory processes in tumor promotion. In the current study, we treated three oral squamous cell carcinoma (OSCC) cell lines with TNF-α to study its role in inflammation-induced tumor progression. Here we show that TNF-α induces stabilization of the transcriptional repressor Snail and activates NF-κB pathway in the three OSCC cell lines. These activities resulted in the increased motility and invasiveness of three OSCC cell lines. In addition, upon dealing with TNF-α for the indicated time, three OSCC cell lines underwent epithelial-to-mesenchymal transition (EMT), in which they presented a fibroblast-like phenotype and had a decreased expression of epithelial marker (E-cadherin) and an increased expression of mesenchymal marker (vimentin). We further demonstrated that TNF-α can up-regulate the expression of Id2 while inducing an EMT in oral cancer cells. Finally, we showed that Id2 interacted with Snail which may constrain Snail-dependent suppression of E-cadherin. In conclusion, our study indicates that TNF-α induces Snail stabilization is dependent on the activation of NF-κB pathway and results in increasing cell invasion and migration in OSCC cells. Id2 may contribute to regulate the function of Snail during TNF-α-mediated EMT in OSCC. These findings have significant implications for inflammation-induced tumor promotion in OSCC.
PMCID: PMC4497435  PMID: 26175937
Epithelial-to-mesenchymal transition; Id2; oral squamous cell carcinoma; Snail; tumor necrosis factor-α
12.  Circulating miRNAs is a potential marker for gefitinib sensitivity and correlation with EGFR mutational status in human lung cancers 
American Journal of Cancer Research  2015;5(5):1692-1705.
miRNA expression is deregulated in non-small cell lung cancer (NSCLC), and some miRNAs are associated with gefitinib sensitivity. Here, we investigated if circulating miRNAs could be a useful biomarker for the prediction of EGFR mutation and the patient’s prognosis. The differential miRNAs related to gefitinib sensitivity were screened and identified by microRNA array. Using Taqman-based real-time RT-PCR, we analyzed the expression of selected miRNAs in tumor tissues and plasma of 150 NSCLC patients. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to determine the association between miRNAs expression and survival. Receiver operating characteristic curve analysis was also performed. Compared with PC9 cell line, 41 microRNAs detected by microarray were significantly differentially expressed in A549 and H1299 cells. The 5 selected hsa-miRNAs were all found differently expressed between wild and mutant EGFR carriers (all P<0.01). Down-regulation of 5 selected miRNAs were independently associated with lymphatic invasion (all P<0.01) and clinical stage (all P<0.01), respectively. Both down-regulation of has-miR-195 (P=0.012) and has-miR-21 (P=0.004) were associated with poor differentiation. All up-regulation of 5 has-miRNAs were associated with smoking (All P<0.05). 5 hsa-miRNAs were up-regulated both in plasma and tissue samples. A model including 4 hsa-miRNAs may predict EGFR mutational status and gefitinib-sensitivity (both AUC: 0.869). Plasma levels of has-miR-125b expression were associated with disease-free survival (P=0.033) and overall survival in the patients (P=0.028). In a word, Circulating 5 selected miRNAs may especially be useful in predicting EGFR mutation, and circulating hsa-miR-125b may have prognostic values in NSCLC patients.
PMCID: PMC4497436  PMID: 26175938
Non-small cell lung cancer (NSCLC); miRNAs; EGFR mutation; gefitinib; acquired resistance
13.  Down regulation of MiR-93 contributes to endometriosis through targeting MMP3 and VEGFA 
American Journal of Cancer Research  2015;5(5):1706-1717.
Objective: This study aimed to explore the role of miRNAs in pathogenesis of endometriosis. Methodology: Endometrial samples from 57 females with endometriosis and 44 non-endometriotic controls were compared for the expression of a selected group of miRNAs. The regulatory function on downstream target was also explored. Results: The expression of miR-93 and miR106a was significantly reduced in endometriotic samples compared to that in non-endometriotic samples. High levels of MMP3 and VEGFA were detected in more than 50% ectopic endometrium tissues. A negative association was found between the expression of miR-93 and the protein levels of MMP3 (Pearson correlation, r=-0.39, P=0.0025) or VEGFA (Pearson correlation, r=-0.37, P=0.0047) in samples from endometriosis patients. Mechanistically, miR-93 targeted MMP3 and VEGFA by directly binding to the 3’UTR of MMP3 and VEGFA mRNAs, and thereby inhibited the proliferation, migration and invasive capability of endometrial stromal cells (ESCs). Conclusion: The finding of this study suggests that deregulation of miR-93 contribute to endometriosis by up-regulation of MMP3 and VEGFA and thus provide potential therapeutic targets for the treatment of endometriosis.
PMCID: PMC4497437  PMID: 26175939
Endometriosis; microRNA; proliferation; migration; invasion
14.  Overexpression of tumor suppressor protein OSCP1/NOR1 induces ER stress and apoptosis during development of Drosophila melanogaster  
American Journal of Cancer Research  2015;5(5):1718-1729.
OSCP1/NOR1 (organic solute carrier partner 1/oxidored-nitro domain-containing protein 1) is known as a transporter of various organic solutes into cells and also is reported to act as a tumor suppressor protein. Although overexpression of OSCP1 has been shown to play multiple roles in mammalian cell lines, its biological significance in living organisms is not fully understood. To explore the effects of OSCP1/NOR1 on development, we performed genetic studies in flies featuring overexpression of its Drosophila orthologue, dOSCP1. Overexpression of dOSCP1 in eye imaginal discs induced a rough eye phenotype in adult flies, likely resulting from a delay in S phase progression and induction of caspase-dependent apoptosis followed by compensatory proliferation. However, it did not appear to be involved in differentiation of R7 photoreceptor cells. We also found that overexpression of dOSCP1 caused endoplasmic reticulum stress in salivary gland cells. These results indicate that overexpression of dOSCP1 exerts effects on various biological processes during Drosophila development.
PMCID: PMC4497438  PMID: 26175940
OSCP1/NOR1; apoptosis; proliferation; ER stress
15.  Overexpression of NDC80 is correlated with prognosis of pancreatic cancer and regulates cell proliferation 
American Journal of Cancer Research  2015;5(5):1730-1740.
Aims: NDC80/Hec1, one of four proteins of the outer kinetochore NDC80 complex, is involved in the tumorigenesis of a variety of cancers. In this study, we focused on that NDC80 is overexpressed in human pancreatic cancer and investigates the role of NDC80-knockdown in pancreatic cancer cells proliferation. Materials and methods: We determined the expression levels of NDC80 on both mRNA and protein levels in fresh pancreatic cancer tissues and cells by quantitative real-time polymerase chain reaction and immunoblotting, respectively. Furthermore, protein level of NDC80 was identified using immunochemistry in paraffin-embedded tumor specimen, with correlation between NDC80 expression and various clinicopathological parameters evaluated. The role of NDC80 in pancreatic cancer cells (Panc-1) growth was investigated by lentivirus-mediated silencing of NDC80. The effect of NDC80 deletion on cell proliferation was analyzed by MTT assay and clone formation assay, while cell cycle distributions and apoptosis were analyzed by flow cytometry. Results: The mRNA and protein of NDC80 were overexpressed in pancreatic cancer tissues and cells. The statistical analysis based on immunohistochemical evaluation suggested that NDC80 overexpression was signifi cantly associated with clinicopathological parameters including pathological T staging and N staging, which may be served as an predictor for poor outcomes. The silencing of NDC80 in Panc-1 cells could suppress cell proliferation and colony formation. Furthermore, the NDC80-siRNA infected Panc-1 cells lead to cell cycle arrest at G2/M phase and induction of apoptosis. Conclusion: These results demonstrated that NDC80 plays an essential role in the tumorigenesis of pancreatic cancer, and might serve as potential prognostic and therapeutic target for treatment of pancreatic cancer.
PMCID: PMC4497439  PMID: 26175941
NDC80; pancreatic cancer; proliferation; apoptosis
16.  AGE/RAGE/Akt pathway contributes to prostate cancer cell proliferation by promoting Rb phosphorylation and degradation 
American Journal of Cancer Research  2015;5(5):1741-1750.
Metabolomic research has revealed that metabolites play an important role in prostate cancer development and progression. Previous studies have suggested that prostate cancer cell proliferation is induced by advanced glycation end products (AGEs) exposure, but the mechanism of this induction remains unknown. This study investigated the molecular mechanisms underlying the proliferative response of prostate cancer cell to the interaction of AGEs and the receptor for advanced glycation end products (RAGE). To investigate this mechanism, we used Western blotting to evaluate the responses of the retinoblastoma (Rb), p-Rb and PI3K/Akt pathway to AGEs stimulation. We also examined the effect of knocking down Rb and blocking the PI3K/Akt pathway on AGEs induced PC-3 cell proliferation. Our results indicated that AGE-RAGE interaction enhanced Rb phosphorylation and subsequently decreased total Rb levels. Bioinformatics analysis further indicated a negative correlation between RAGE and RB1 expression in prostate cancer tissue. Furthermore, we observed that AGEs stimulation activated the PI3K/Akt signaling pathway and that blocking PI3K/Akt signaling abrogated AGEs-induced cell proliferation. We report, for the first time, that AGE-RAGE interaction enhances prostate cancer cell proliferation by phosphorylation of Rb via the PI3K/Akt signaling pathway.
PMCID: PMC4497440  PMID: 26175942
AGEs; RAGE; prostate cancer; proliferation; retinoblastoma; Akt
17.  Inhibition of STAT3 reduces proliferation and invasion in salivary gland adenoid cystic carcinoma 
American Journal of Cancer Research  2015;5(5):1751-1761.
In this study, we accessed the expression and correlation of p-STAT3 with Survivin, Cyclin D1, CD147, Slug and Ki67 by immunohistochemical staining of human tissue microarray which contains 72 adenoid cystic carcinoma (AdCC), 12 pleomorphic adenoma (PMA) and 18 normal salivary gland (NSG) using digital pathological scanner and scoring system. We found that the expression of p-STAT3, Survivin, Slug, Cyclin D1 and CD147 was significantly increased in AdCC as compared with PMA and (or) NSG (p<0.05). While, the level of p-STAT3 and expression of Cyclin D1 and CD147 was not associated with pathological type of human AdCC (p>0.05). Correlation analysis of these proteins revealed that p-STAT3 up-regulates the expression of Survivin, Slug, Cyclin D1 and CD147 (p<0.05). Moreover, the activation of STAT3 was associated with proliferation marker Ki-67 (p<0.05). Selective inhibition of STAT3 by a small molecule S3I-201 significantly reduced human SACC-83 and SACC-LM cells proliferation, migration and invasion with the corresponding decrease in expression of Survivin, Slug, Cyclin D1 and CD147. These findings indicate that high phosphorylation level of STAT3 in AdCC is related to Survivin, Slug, Cyclin D1 and CD147. We suggest that the inhibition of STAT3 may be a novel strategy for neoadjuvant chemotherapeutic treatment of AdCC.
PMCID: PMC4497441  PMID: 26175943
STAT3; Cyclin D1; CD147; adenoid cystic carcinoma; S3I-201
18.  Loss of FGF21 in diabetic mouse during hepatocellular carcinogenetic transformation 
American Journal of Cancer Research  2015;5(5):1762-1774.
Diabetes associated metabolic syndrome has been shown to be an independent risk factor for the development of hepatocellular carcinoma (HCC). Cirrhosis, in fact, was not always a prerequisite of HCC development and this might particularly apply to the metabolic abnormality associated HCC. This study was to investigate diabetes associated HCC and the potential role of FGF21 during carcinogenetic transformation of HCC. Dimethylnitrosamine (DEN) was used to induce HCC in the diabetic OVE26 mice. Pronounced damage characterized by steatohepatitis was found in the liver of diabetic mice. Steatohepatitis accompanied by constant cell proliferation and tumor cell growth were also found in the hepatic tissues of diabetic OVE26 mice when DEN being administrated. FGF21 protein level increased in liver tissues at an early stage along with steatohepatitis in diabetic OVE26 mice, but decreased in liver tissues later when HCC was developed. In addition, decreased FGF21 protein level was associated with cancerous hyper-proliferation and aberrant p53 and TGF-β/Smad signaling during HCC development. Loss of FGF21 may play an important role in HCC carcinogenetic transformation during metabolic liver injury in diabetic animals. The present finding calls attention to the need to control metabolic disorders associated with diabetes and may further develop a protective strategy against HCC.
PMCID: PMC4497442  PMID: 26175944
Hepatocellular carcinoma; diabetes; OVE26 mice; dimethylnitrosamine; FGF21
19.  GPX3 hypermethylation serves as an independent prognostic biomarker in non-M3 acute myeloid leukemia 
American Journal of Cancer Research  2015;5(5):1786-1794.
Hypermethylation of GPX3 (glutathione peroxidase 3) promoter has been identified in various solid tumors. However, the pattern of GPX3 promoter methylation in acute myeloid leukemia (AML) remains poorly known. The current study was intended to investigate the clinical significance of GPX3 promoter methylation in de novo AML patients and further determine its role in regulating GPX3 expression. GPX3 promoter methylation status in 181 de novo AML patients and 44 normal controls was detected by real-time quantitative methylation-specific PCR and bisulfite sequencing PCR. Real-time quantitative PCR was carried out to assess GPX3 expression. GPX3 promoter was significantly methylated in 181 AML patients compared with normal controls (P=0.022). The patients with GPX3 methylation presented significantly older age than those with GPX3 unmethylation (P=0.011). GPX3 methylated patients had significantly lower frequency of C/EBPA mutation and higher incidence of FLT3-ITD mutation (P=0.037 and 0.030). The non-M3 patients with GPX3 methylation had significantly lower overall survival than thoes with GPX3 unmethylation (P=0.036). No significant correlation was observed between GPX3 expression and its promoter methylation (R=0.110, P=0.284). However, GPX3 mRNA level was significantly increased after 5-aza-2’-deoxycytidine treatment in leukemic cell line THP1. GPX3 methylation predicts adverse clinical outcome in non-M3 AML patients. Moreover, GPX3 expression is regulated by its promoter methylation in leukemic cell line THP1.
PMCID: PMC4497444  PMID: 26175946
GPX3; methylation; prognosis; regulation; acute myeloid leukemia
20.  Tumor-suppressive microRNA-497 targets IKKβ to regulate NF-κB signaling pathway in human prostate cancer cells 
American Journal of Cancer Research  2015;5(5):1795-1804.
Background: Prostate cancer (PCa) is one of the most prevalent malignant tumors, PCa-related death is mainly due to the high probability of metastasis. MicroRNAs (miRNAs) play an important role in cancer initiation, progression and metastasis by regulating their target genes. Methods: real-time PCR was used to detected the expression of microRNA-497. The molecular biological function was investigated by using cell proliferation assays, cell cycle assay, and migration and invasion assay. We used several Algorithms and confirmed that IKKβ is directly regulated by miR-497. Results: Here, we found miR-497 is downregulated in human prostate cancer (PCa) and inhibites the proliferation activity, migration and invasion of PC3-AR cells. Subsequently, IKKβ is confi rmed as a target of miR-497. Furthermore, knockdown of IKKβ expression resulted in decreased proliferation activity, migration and invasion. Finally, similar results was found after treatment with a novel IKK-β inhibitor (IMD-0354) in PC3-AR cells. CDK8, MMP-9, and PSA were involved in all these process. Conclusion: Taken together, our results show evidence that miR-497 may function as a tumor suppressor genes by regulating IKK-β in PCa, and may provide a strategy for blocking PCa metastasis.
PMCID: PMC4497445  PMID: 26175947
MiR-497; PCa; IKKβ; IMD-0354; migration; invasion
21.  Decrease of Bcl-xL/Bcl-2-associated death promoter in hepatocellular carcinoma indicates poor prognosis 
American Journal of Cancer Research  2015;5(5):1805-1813.
Bcl-xL/Bcl-2-associated death promoter (Bad) is a proapoptotic member of Bcl-2 family and plays a key role in tumor development. To explore the expression of Bad and its clinical significance in hepatocellular carcinoma (HCC), we analyzed a large cohort of 437 HCC samples by tissue microarray (TMA)-based immunohistochemistry. Our data showed that Bad expression was markedly decreased in 50.6% (221/437) of HCC tissues, compared with the adjacent nontumorous tissues. Bad expression was closely associated with adverse clinical characters such as clinical stage (P=0.007), tumor size (P=0.008), vascular invasion (P=0.024), tumor differentiation (P=0.018) and AFP level (P=0.039). Furthermore, Kaplan-Meier analysis indicated that low Bad expression was significantly correlated to overall survival (P<0.0001) but not disease-free survival (P=0.587) and recurrence-free survival (P=0.707) of patients with HCC. Stratified survival analysis further confirmed the prognostic value of Bad. Moreover, multivariate analyses revealed that Bad was an independent indicator of overall survival in HCC (hazard ration=0.589, 95% confidence interval: 0.483-0.717, P<0.0001). Collectively, our data suggest that Bad is down-regulated in HCC and serves as a promising biomarker for poor prognosis of patients with this fatal disease.
PMCID: PMC4497446  PMID: 26175948
Bad; BCL-2; poor prognosis; hepatocellular carcinoma
22.  FBXO31 promotes cell proliferation, metastasis and invasion in lung cancer 
American Journal of Cancer Research  2015;5(5):1814-1822.
FBXO31 is a member of F-box family which is involved in diverse biological functions and development of disease. Recent reports in breast cancer, hepatocellular carcinoma and ovarian cancer demonstrated inhibitory effect of FBXO31 on proliferation and tumorigenesis. However, the function of FBXO31 is not analyzed in lung cancer so far. In this study, we reported that expression of FBXO31 was higher in lung cancer tissues compared with non-cancerous lung tissues, and that higher expression of FBXO31 was significantly associated with tumor size, tumor infiltration, clinical stages and lymph node metastasis. In addition, exogenous expression of FBXO31 promoted cell growth, metastasis and invasion in A549 cells. Conversely, silencing FBXO31 by specific siRNA caused inhibitory effect on cell growth, metastasis and invasion. Moreover, tumorigenicity assays in nude mice showed FBXO31 promoted tumor growth in vivo. In conclusion, our data suggest FBXO31 promotes cell proliferation, metastasis and invasion in lung cancer.
PMCID: PMC4497447  PMID: 26175949
FBXO31; tumor growth; metastasis; invasion; lung cancer
23.  Six1 promotes glioblastoma cell proliferation and invasion by upregulation of connective tissue growth factor 
American Journal of Cancer Research  2015;5(5):1823-1830.
Glioblastoma multiforme (GBM) is the deadliest and most common form of malignant primary brain tumor in humans. However, until now, little is known about the glioma genesis and progression at the molecular level. Here we report that overexpression of sine oculis homeobox homolog 1 (Six1), a developmental transcription factor implicated in tumor onset and progression, can significantly promote glioblastoma cell proliferation and invasion by upregulating connective tissue growth factor (CTGF). Our results revealed that expression of Six1 mRNA was increased and small hairpin RNAi silencing of Six1 could dramatically inhibit cell proliferation and invasion in GBM. Moreover, it was found that CTGF gene could be transcriptionally regulated by Six1. Its overexpression induced CTGF up-regulation in GBM at both the mRNA and protein level, and significantly enhanced the activity of CTGF promoter in these tumor cells, while decreasing CTGF expression impeded Six1-induced cell proliferation and invasion, revealing that CTGF is required for Six1-mediated GBM growth and metastasis. Collectively, these findings suggest that Six1 overexpression may contribute to cell proliferation and invasion via upregulation of CTGF in GBM. Our study provides new insights into the important roles of Six1 and CTGF in tumor regulation, suggesting that Six1 might be a potential therapeutic target for preventing proliferation and metastasis of GBM.
PMCID: PMC4497448  PMID: 26175950
Six1; CTGF; glioblastoma; cell proliferation; invasion
24.  A simple and effective prognostic staging system based on clinicopathologic features of intrahepatic cholangiocarcinoma 
American Journal of Cancer Research  2015;5(5):1831-1843.
Incidence and mortality of intrahepatic cholangiocarcinoma (ICC) are increasing. However, its prognostic predictive system associated with outcome after surgery remains poorly defined. In this study, we conducted retrospective survival analyses in a primary cohort of 370 patients who underwent partial hepatectomy for ICC (2005 and 2009). We found that seven variables were significantly independent predictors for overall survival (OS): serum prealbumin (hazard ratio [HR]: 1.447; p = 0.015), carbohydrate antigen 19-9 (HR: 1.438; p = 0.009), carcinoembryonic antigen (HR: 1.732; p = 0.002), tumor number (HR: 1.781; p < 0.001), vascular invasion (HR: 1.784; p < 0.001), regional lymphatic metastasis (HR: 2.003; p < 0.001) and local extrahepatic metastasis (HR: 1.506; p = 0.008). Using these independent predictors, we created a simple clinicopathologic prognostic staging system for predicting survival of ICC patients after resection. The validity of the prognostic staging system was prospectively assessed in 115 patients who underwent partial hepatectomy between January 2010 and December 2010 at the same institution. The prognostic power was quantified using likelihood ratio test and Akaike information criteria. Compared with the 6th and 7th AJCC staging systems, the new staging system in the primary cohort had a higher predictive accuracy for OS in terms of homogeneity and discriminatory ability. In the validation cohort, the homogeneity and discrimination of the new staging system were also superior to the two other staging systems. Conclusions: The new staging system based on clinicopathologic features may provide relatively higher accuracy in prognostic prediction for ICC patients after tumor resection.
PMCID: PMC4497449  PMID: 26175951
Intrahepatic cholangiocarcinoma; clinicopathologic features; prognosis; staging system; partial
25.  Apoptosis pathway signature for prediction of treatment response and clinical outcome in childhood high risk B-Precursor acute lymphoblastic leukemia 
American Journal of Cancer Research  2015;5(5):1844-1853.
The most common cancer in children is acute lymphoblastic leukemia (ALL) and it had high cure rate, especially for B-precursor ALL. However, relapse due to drug resistance and overdose treatment reach the limitations in patient managements. In this study, integration of gene expression microarray data, logistic regression, analysis of microarray (SAM) method, and gene set analysis were performed to discover treatment response associated pathway-based signatures in the original cohort. Results showed that 3772 probes were significantly associated with treatment response. After pathway analysis, only apoptosis pathway had significant association with treatment response. Apoptosis pathway signature (APS) derived from 15 significantly expressed genes had 88% accuracy for treatment response prediction. The APS was further validated in two independent cohorts. Results also showed that APS was significantly associated with induction failure time (adjusted hazard ratio [HR] = 1.60, 95% confidence interval [CI] = [1.13, 2.27]) in the first cohort and significantly associated with event-free survival (adjusted HR = 1.56, 95% CI = [1.13, 2.16]) or overall survival in the second cohort (adjusted HR = 1.74, 95% CI = [1.24, 2.45]). APS not only can predict clinical outcome, but also provide molecular guidance of patient management.
PMCID: PMC4497450  PMID: 26175952
Acute lymphoblastic leukemia; apoptosis; gene signature; prediction and clinical outcome

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