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1.  Autologous bone marrow stem cell transplantation for the treatment of postoperative hand infection with a skin defect in diabetes mellitus: A case report 
Oncology Letters  2014;7(6):1857-1862.
Among stem cells, autologous mesenchymal stem cells (MSCs) are ideal for transplantation by virtue of limited rejection reactions and marked proliferative ability. This study presents a novel method by which MSCs were harvested from the bone marrow of a patient who presented with severe post-traumatic infection and a non-healing skin defect in the hand, secondary to uncontrolled diabetes mellitus (DM). An autologous MSC suspension was injected into the persistent skin defect after stabilizing the blood glucose level and appropriate infection control. During the course of a regular 18-month postoperative follow-up, the patient exhibited immediate recovery with no transplant-associated complications, as well as no evidence of tumorigenicity. Thus, transplantation of autologous MSCs may play a role in the clinical application of stem cells, particularly for treatment of skin defects following surgery in cases of DM and for those caused by various other traumas.
doi:10.3892/ol.2014.1998
PMCID: PMC4049741  PMID: 24932248
bone marrow mesenchymal stem cell; autotransplantation; diabetes mellitus; skin defect; tumorigenicity
2.  Identification and characterization of tumor suppressor and oncogenic miRNAs in gastric cancer 
Oncology Letters  2015;10(1):329-336.
The aim of the present study was to screen for and identify microRNAs (miRNAs/miRs) that are associated with gastric cancer and to clarify the role of these miRNAs in gastric cancer. Thus, the differential expression of a panel of miRNAs in two pairs of gastric cancer tissues and their matched adjacent healthy tissues was investigated by performing a microarray analysis. To verify the results of this screen, 56 gastric cancer tissues were analyzed for the selected miRNAs using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The association between the expression of a specific miRNA and the clinical data relating to the tissue samples [including age, gender, tumor size, tumor node metastasis (TNM) stage and lymph-node metastasis] were subsequently examined. A total of 31 differentially expressed miRNAs were identified in the miRNA array. Using RT-qPCR to verify these results, it was determined that 10 miRNAs exhibited high mRNA expression levels and 13 miRNAs exhibited a low expression in the gastric cancer tissue samples, while 8 miRNAs did not demonstrate an association with gastric cancer. Thus, the microarray and RT-qPCR results demonstrated 74.2% (23/31 miRNAs) agreement. The association between the 23 miRNAs and the clinicopathological characteristics of the gastric cancer samples was investigated. It was identified that the expression levels of miR-551b-3p, miR-133b, miR-100-5p and miR-363-3p were significantly downregulated in the gastric cancer tissues, and this downregulation was closely correlated with the degree of differentiation (i.e., tumor grade), TNM stage and lymph-node metastasis (P<0.05). By contrast, the expression of miR-215 was significantly upregulated in the gastric cancer tissues, and its expression level was correlated with tumor differentiation, TNM stage and lymph-node metastasis (P<0.05). Furthermore, miR-200a-3p was upregulated in the gastric cancer tissues and its expression was significantly more prevalent in male patients compared with female patients (P<0.05). miR-429 was upregulated in the gastric cancer tissues and its expression was significantly higher in patients who were >50 years of age (P<0.05). These data indicate that a number of these miRNAs may be important in the development of gastric cancer. In particular, miR-551b-3p, miR-133b, miR-100-5p and miR-363-3p may act as tumor suppressors in the development of gastric cancer. By contrast, miR-215 appears to exhibit oncogenic properties and promote the development of gastric cancer. In addition, the abnormal expression of miR-200a-3p may be associated with gender, while the abnormal expression of miR-429 may be associated with age in patients with gastric cancer. However, additional studies are required to delineate the underlying mechanisms of the association, and to explore their potential as valid biomarkers in the diagnosis, classification and prognosis of gastric cancer.
doi:10.3892/ol.2015.3179
PMCID: PMC4487161  PMID: 26171025
gastric cancer; microRNA; clinical pathology
3.  DCF intraperitoneal and intravenous dual chemotherapy regimen for advanced gastric cancer: A feasibility study 
Oncology Letters  2014;9(1):491-497.
Gastric cancer is the fourth most common type of cancer globally and accounts for the second highest cancer-associated mortality rate in the world. Current treatment strategies for gastric cancer include surgery, radiotherapy, chemotherapy and targeted therapy. Intraperitoneal (IP) chemotherapy may increase the IP concentrations of chemotherapy drugs and reduce the systemic toxicity. At present, IP chemotherapy is used to treat patients with advanced gastric cancer, which has a high rate of peritoneal recurrence. The present study evaluated the feasibility of using docetaxel, cisplatin and fluorouracil (DCF) in an IP and intravenous (IV) dual chemotherapy regimen for the treatment of advanced gastric cancer. The treatment-associated adverse reactions and preliminary efficacy were reported. The first dose level utilized the full dose of DCF: Docetaxel, day one, 45 mg/m2 (IP) and day eight, 30 mg/m2 (IV); cisplatin (DDP), day one, 75 mg/m2 (IP); and fluorouracil (FU), days one to five, 750 mg/m2 (continuous IV). A total of six patients were treated at this level and two patients withdrew due to serious adverse reactions. Taking into account that the the tolerated doses used in combination regimens for Eastern populations are lower than that of the corresponding doses for Western populations, the dosages of the three drugs were all reduced by 20% in the application of the second dose level: Docetaxel, day one, 30 mg/m2 (IP) and day eight, 30 mg/m2 (IV); DDP, day two, 60 mg/m2 (IP); and FU, days one to five, 600 mg/m2 (continuous IV). A total of 26 patients were treated at this level. The main adverse reaction was bone marrow suppression, with grade III/IV neutropenia, leukopenia and febrile neutropenia accounting for 61.5, 53.8 and 19.2% of reactions, respectively, and grade III/IV anemia and thrombocytopenia accounting for 19.2 and 15.4% of reactions, respectively. Gastrointestinal adverse reactions primarily consisted of abdominal pain, with grade III/IV abdominal pain accounting for 30.8% of reactions. Only 7.7% of the patients withdrew from the treatment. The median time to progression (TTP) was five months [95% confidence interval (CI), 1.0–9.0 months], and the median overall survival (OS) was nine months (95% CI, 7.4–10.6 months). It was concluded that the DCF regimen with reduced dosage should be applied. IP and IV dual chemotherapy for the treatment of unresectable advanced gastric cancer is tolerated and demonstrated a good initial efficacy. Strategies for mitigating and reducing the adverse gastrointestinal reactions, particularly abdominal pain, may be the focus of future studies.
doi:10.3892/ol.2014.2651
PMCID: PMC4246631  PMID: 25436015
gastric cancer; intraperitoneal chemotherapy; dual chemotherapy; docetaxel; cisplatin; fluorouracil
4.  Human leukocyte antigen-haploidentical donor-derived cytokine-induced killer cells are safe and prolong the survival of patients with advanced non-small cell lung cancer 
Oncology Letters  2014;8(6):2727-2733.
The aim of the present study was to evaluate the safety and efficacy of administering cytokine-induced killer cells (termed allogeneic CIKs), obtained from the blood of the offspring of patients, for the treatment of non-small cell lung cancer. Symptoms, signs and laboratory assessment results for 303 cancer patients were collected prior to and following treatment with autologous or allogeneic CIKs. In addition, 54 patients with advanced non-small cell lung cancer (NSCLC) were enrolled and divided into allogeneic CIK and optimal support groups (n=27 per group) according to gender, age, Karnofsky performance status score, TNM stage and histological type. In addition, overall survival (OS) was compared between the two groups. A total of 303 patients were treated with CIKs for 647 cycles, with 308 and 339 cycles in the autologous and allogeneic CIK groups, respectively. The mean number of CIKs in the autologous and allogeneic groups was 2.11±0.32×1010 and 2.29±0.36×1010, respectively, with no marked differences identified between the two groups (t=1.147; P>0.05). The predominant adverse events included insomnia, fever, nausea, vomiting and mild abdominal pain, which were found, respectively, in nine (6.8%), eight (6.0%), two (1.5%) and one (0.8%) patients receiving autologous CIKs and 11 (6.5%), 10 (5.9%), one (0.6%) and one (0.6%) patients receiving allogeneic CIKs, with no marked differences identified between the two groups (P>0.05). Adverse events were not associated with cell count, frequency or duration of treatment. Following CIK treatment, the outcomes of routine blood tests, and liver and kidney function tests, as well as immune function and electrocardiogram examinations remained unchanged (P>0.05). The median OS was 11.0 months (95% confidence interval (CI), 8.6–13.4 months) and 8.0 months (95% CI, 5.3–10.7 months) for NSCLC patients receiving allogeneic CIKs and optimal support, respectively; a statistically significant difference was identified (χ2=5.618; P=0.018). The present study demonstrated that CIKs from human leukocyte antigen haploidentical donors are safe and prolong the survival of NSCLC patients.
doi:10.3892/ol.2014.2558
PMCID: PMC4214449  PMID: 25364456
cytokine-induced killer cells; immunotherapy; adoptive; allogeneic; malignant tumor; carcinoma; non-small cell lung
5.  Limb salvage surgery following resection of a melanoma: Foot and ankle reconstruction using cutaneous flaps 
Oncology Letters  2014;8(5):1966-1972.
Melanomas affect the foot and ankle region and are associated with a poor prognosis. The aim of the current study was to evaluate the functional and oncological outcomes of salvage surgery using cutaneous flaps for soft tissue reconstruction of the foot and ankle following the extended resection of a melanoma. A retrospective review was conducted to evaluate patients who presented with foot melanoma and underwent salvage surgery and defect reconstruction using three types of cutaneous flap (group S) or amputation (group A) between January 1999 and December 2010 at the First Hospital of Jilin University (Changchun, China). The postoperative mortality, surgical complications, functional outcomes and oncological outcomes were evaluated. Of the 21 patients, 11 were enrolled into group S and 10 were enrolled into group A. The median follow-up time of the patients was 58 months (range, 6–92 months). In group S, a reverse sural neurocutaneous island flap was used in six patients to perform the foot reconstruction, medial plantar flaps were used in four patients and lateral malleolus flaps were used in one patient. All 11 cutaneous flaps survived and provided satisfactory coverage. Only one cutaneous flap showed partial necrosis and required treatment comprising of debridement and regular changes to the wound dressing. The overall survival rate of patients was 65.0% and patients in the two groups experienced similar oncological outcomes. Salvage surgery with cutaneous flap reconstruction was found to be a reliable option for patients presenting with malignant melanoma of the foot and ankle.
doi:10.3892/ol.2014.2440
PMCID: PMC4186625  PMID: 25295080
cutaneous flaps; foot and ankle; malignant melanoma; salvage surgery; soft tissue defects
6.  Interfering with CXCR4 expression inhibits proliferation, adhesion and migration of breast cancer MDA-MB-231 cells 
Oncology Letters  2014;8(4):1557-1562.
To investigate the effect and mechanism of the CXC chemokine receptor 4 (CXCR4) in the proliferation and migration of breast cancer, a short-hairpin RNA (shRNA) eukaryotic expression vector targeting CXCR4 was constructed, and the impact of such on the proliferation, adhesion and migration of human breast cancer MDA-MB-231 cells was observed. The fragments of CXCR4-shRNA were synthesized and cloned into a pGCsi-U6-Neo-green fluorescent protein vector. The recombinant plasmids were transfected into 293T cells and the most efficacious interfering vector was selected. MDA-MB-231 cells were transfected by liposome assay. The effects of silencing CXCR4 expression by shRNA on the growth, adhesion and migration of MDA-MB-231 cells were determined by Cell Counting Kit-8, cell-matrix adhesion and wound-healing assays. The shRNA eukaryotic expression vectors targeting CXCR4 (CXCR4-shRNA) were successfully constructed and transfected into 293T cells. Quantitative polymerase chain reaction and western blot analysis revealed that the maximum inhibitory rate of CXCR4 expression was 81.3%. CXCR4-shRNA transfection significantly inhibited the proliferation of MDA-MB-231 cells (P<0.05), as well as the adhesion between MDA-MB-231 cells and the extracellular matrix (P<0.05). Furthermore, wound-healing assays demonstrated that the migration distance of MDA-MB-231 cells in the CXCR4-shRNA transfection group was significantly smaller than that in the control plasmid and blank control groups (P<0.01). The CXCR4-shRNA interfering vector specifically inhibited CXCR4 expression, as well as the proliferation, adhesion and migration of MDA-MB-231 cells.
doi:10.3892/ol.2014.2323
PMCID: PMC4156168  PMID: 25202367
CXC chemokine receptor 4; RNA interference; breast cancer
7.  Synergistic killing of lung cancer cells by cisplatin and radiation via autophagy and apoptosis 
Oncology Letters  2014;7(6):1903-1910.
Cisplatin is a commonly used drug for chemotherapy, however, whether it may be used synergistically with radiotherapy remains unclear. The present study investigated the underlying mechanisms of synergistic killing by radiosensitization and cisplatin, with a focus on the growth inhibition, apoptosis and autophagy of non-small cell human lung cancer cells in vitro and in a tumor xenograft in vivo. A549 cells were used for the in vitro experiments and divided into the following four treatment groups: Sham-irradiated; conventional radiotherapy (CRT) of five doses of 2 Gy every day; hyperfractionated radiotherapy of five doses of 2 Gy (1 Gy twice a day at 4 h intervals) every day; and CRT plus cisplatin. A xenograft tumor-bearing C57BL/6 model was established for the in vivo experiments and the above-mentioned treatments were administered. MTT and colony formation assays were used to detect cell viability and western blotting was performed to detect the levels of protein expression. Monodansylcadaverine staining and the immunofluorescence technique were used to analyze the autophagy rate, while flow cytometry and immunohistochemistry were performed to detect the expression levels of the genes associated with apoptosis and autophagy, including microtubule-associated protein 1 light chain 3 (MAPLC3)-II, phosphoinositide 3-kinase (PI3K) III, Beclin1, phosphorylated protein kinase B (p-AKT), damage-regulated autophagy modulator (DRAM), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, caspase-3 and p21. The MTT assay demonstrated that cisplatin exhibits a dose-dependent cytotoxicity in A549 cells and synergizes with radiation to promote the cell-killing effect of radiation. In the xenograft mouse model of Lewis cells, cisplatin plus ionizing radiation (IR) (five doses of 2 Gy) yielded the most significant tumor suppression. The autophagic vacuoles, the ratio of MAPLC3-II to MAPLC3-I (LC3-II/LC3-I) and the levels of Beclin1 were found to increase in all treatment groups, with the most marked upregulation observed in the CRT plus cisplatin treatment group. In addition, caspase-3 processing was enhanced in the group treated with the combination of cisplatin with radiation, compared with the group treated with radiation alone. Fractionated IR resulted in a significant increase in p21 expression, which was further enhanced when combined with cisplatin. Furthermore, treatment with cisplatin and fractionated IR resulted in a significant elevation of the expression of the autophagy-related genes, PI3KIII, Beclin1 and DRAM1. However, the levels of p-AKT were observed to decline following exposure to fractionated IR in the presence or absence of cisplatin. As for the apoptosis signaling genes, the combination of cisplatin and fractionated IR therapy resulted in a significant decrease in Bcl-2 expression and a marked upregulation of p21 expression. The current study offers strong evidence that the combination of cisplatin with radiation strengthens the killing effect of radiation via pro-apoptotic and pro-autophagic cell death.
doi:10.3892/ol.2014.2049
PMCID: PMC4049698  PMID: 24932256
cisplatin; radiosensitivity; synergistic killing; lung cancer; autophagy; apoptosis
8.  Functionally active rat S100A4 from a polymerase chain reaction-synthesized gene expressed in soluble form in Escherichia coli 
Oncology Letters  2014;7(4):1179-1184.
S100A4 protein is associated with Ca2+-dependent regulation of intracellular activities and is significant in the invasion, growth and metastasis of cancer. In order to express rat S100A4 functionally and identify its biological activity following purification, an S100A4 gene fragment was optimized and fully synthesized via overlapping polymerase chain reaction. The gene was inserted into the prokaryotic expression vector, pBV220, with phage λ PRPL promoters following confirmation by DNA sequencing. The pBV220-S100A4 plasmid was constructed and transformed into Escherichia coli DH5α. Following temperature induction, rat S100A4 was overexpressed and the protein was observed to be located in the supernatant of the lysates, which was ~30–40% of the total protein within the host. The protein was isolated and purified by metal-chelate affinity chromatography. High purity protein (>98% purity) was obtained and in vitro western blot analysis identified that the recombinant S100A4 was able to bind to the antibody against wild-type S100A4. The bioactivity of the recombinant protein was detected via Transwell migration and invasion assays. The polyclonal antibody of rat S100A4 protein was prepared for rabbit immunization and exhibited similar efficacies when compared with commercial S100A4. Therefore, rat S100A4 was functionally expressed in E. coli; thus, the production of active recombinant S100A4 protein in E. coli may further aid with the investigation and application of S100A4.
doi:10.3892/ol.2014.1870
PMCID: PMC3961442  PMID: 24944689
rat S100A4; functional expression; gene recombination
9.  Significantly increased expression of OCT4 and ABCG2 in spheroid body-forming cells of the human gastric cancer MKN-45 cell line 
Oncology Letters  2013;6(4):891-896.
The cancer stem cell (CSC) theory hypothesizes that CSCs are the cause of tumor formation, recurrence and metastasis. Key to the study of CSCs is their isolation and identification. The present study investigated whether spheroid body-forming cells in the human gastric cancer (GC) MKN-45 cell line are enriched for CSC properties, and also assessed the expression of the candidate CSC markers, octamer-binding transcription factor-4 (OCT4) and adenosine triphosphate-binding cassette transporter G2 (ABCG2) in the MKN-45 spheroid body cells. The MKN-45 cells were plated in a stem cell-conditioned culture system to allow for spheroid body formation. The expression levels of OCT4 and ABCG2 in the spheroid body cells were assessed by qPCR, western blot analysis and immunofluorescence staining, while the tumorigenicity of the spheroid body-forming cells was assessed by in vivo xenograft studies in nude mice. The MKN-45 cells were able to form spheroid bodies when cultured in stem cell-conditioned medium. The spheroid body-forming cells showed a significantly higher (P<0.01) expression of OCT4 and ABCG2 compared with the parental cells. These data suggest that the spheroid body cells from the MKN-45 GC cell line cultured in stem cell-conditioned medium possessed gastric CSC properties. The co-expression of OCT4 and ABCG2 by these cells may represent the presence of a subpopulation of gastric CSCs.
doi:10.3892/ol.2013.1506
PMCID: PMC3796425  PMID: 24137432
human gastric cancer; cancer stem cell; OCT4; ABCG2
10.  CCN3 (NOV) regulates proliferation, adhesion, migration and invasion in clear cell renal cell carcinoma 
Oncology Letters  2012;3(5):1099-1104.
The CCN3/nephroblastoma overexpressed gene belongs to the CCN family of genes that encode secreted proteins involved in a variety of processes including tumorigenesis. Altered expression of CCN3 has been observed in human nephroblastoma and renal cell carcinoma (RCC), suggesting that CCN3 plays a role in kidney tumorigenesis. The aim of the present study was to examine the role of CCN3 in clear cell RCC biology. In particular, we studied the expression of CCN3 in 32 pairs of RCC tissues and corresponding normal kidney tissues using immunohistochemistry. The CCN3 gene was transfected into the 786-O cell line and the behaviors of stably transfected clones were analyzed. Results showed the expression of CCN3 was lower in RCC tissues compared to corresponding normal kidney tissues and the expression of CCN3 was inversely correlated with the Ki67 index. CCN3-expressing clones exhibited significantly inhibited cell proliferation. Furthermore, CCN3-transfected 786-O cells exhibited increased adhesion to extracellular matrix proteins, migration and invasion in Matrigel. Our data indicated that CCN3 plays an anti-proliferative role in clear cell RCC cells and promotes the adhesion, migration and invasion of clear cell RCC cells.
doi:10.3892/ol.2012.607
PMCID: PMC3389651  PMID: 22783399
renal cell carcinoma; CCN3; migration; tumorigenicity
11.  Effect of integrin receptor-targeted liposomal paclitaxel for hepatocellular carcinoma targeting and therapy 
Oncology Letters  2015;10(1):77-84.
The major aim of the present study was to develop an integrin receptor-targeted liposomal paclitaxel (PTX) to enhance the targeting specificity and therapeutic effect of PTX on hepatocellular carcinoma (HCC) cells. The specific Arg-Gly-Asp (RGD) ligand was conjugated to 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 to prepare the RGD-modified liposomes (RGD-LP). Furthermore, physicochemical characteristics of RGD-LP, including particle size, ζ potential, encapsulation efficiency and in vitro PTX release, were evaluated. RGD-modified liposomes were selected as the carrier for the present study, as they exhibit good biocompatibility and are easy to modify using RGD. The cellular uptake efficacy of RGD-LP by HepG2 cells was 3.3-fold higher than that of liposomes without RGD, indicating that RGD-LP may specifically target HepG2 cells by overexpressing integrin αvβ3 receptors. The RGD modification appeared to enhance the anti-proliferative activity of LP-PTX against HepG2 cells, with the extent of anti-proliferative activity dependent on the concentration of PTX and the incubation time. Additionally, evaluation of the homing specificity and anticancer efficacy of RGD-LP on the tumor spheroids indicated that solid tumor penetration was enhanced by the modification of RGD. In agreement with these in vitro findings, in vivo investigations demonstrated that RGD-LP-PTX exhibited a greater inhibitory effect on tumor growth in HepG2-bearing mice than LP-PTX or free PTX. Thus, RGD-LPs may represent an efficient targeted PTX delivery system for the treatment of patients with HCC.
doi:10.3892/ol.2015.3242
PMCID: PMC4487032  PMID: 26170980
integrin receptor; tumor targeting; paclitaxel; liposome
12.  Levels of bone marrow microvessel density are crucial for evaluating the status of acute myeloid leukemia 
Oncology Letters  2015;10(1):211-215.
The aim of the present study was to determine the efficacy of bone marrow microvessel density (BM-MVD) in the evaluation of the status of acute myeloid leukemia (AML). The levels of serum and bone marrow vascular endothelial growth factor (VEGF), and BM-MVD in 28 patients with AML, 10 patients with non-Hodgkin's lymphoma, 10 patients with anemia and 14 patients with AML that achieved complete remission for six months (AML-DFS) subsequent to chemotherapy were determined by ELISA and immunohistochemistry. The levels of serum VEGF in patients with hematological disorders were significantly increased compared with the levels in the healthy controls. The levels of BM VEGF and BM-MVD in AML patients were significantly higher compared with the levels in the patients with non-Hodgkin's lymphoma or anemia. Following chemotherapy, the levels of serum VEGF significantly increased and the levels of BM VEGF decreased in the AML patients, regardless of their therapeutic responses, compared with the levels prior to treatment. By contrast, the levels of BM-MVD in the AML patients were significantly reduced in the patients that completely recovered from AML (AML-DFS group), compared with those in other groups. The present data indicate that the levels of BM-MVD are valuable for evaluating the status of AML.
doi:10.3892/ol.2015.3209
PMCID: PMC4487085  PMID: 26171001
vascular endothelial growth factor; bone marrow microvessel density; acute myeloid leukemia
13.  Recurrent waist tumor subsequent to percutaneous nephrolithotomy: A case report 
Oncology Letters  2015;10(1):297-300.
The present study reports the case of a 39-year old male patient with a recurrent waist tumor that occurred subsequent to percutaneous nephrolithotomy (PCNL). The patient initially underwent PCNL for the management of right calculus of the kidney. Six years later, the patient underwent local mass resection for a tumor at the waist, which was subsequently diagnosed as adenocarcinoma. However, seven months subsequent to local resection, the patient presented to the Affiliated Cancer Hospital of Xiangya Medical School with a one-month history of a recurrent tumor located at the right waist. Physical examination identified no visible skin lesions; however, a palpable hard nodule was present over the right waist. Imaging studies, consisting of computed tomography (CT) and positron emission tomography-CT, indicated no additional metastases. Therefore, the patient underwent local mass resection of the waist tumor. Subsequent histological examination determined a diagnosis of metastatic adenocarcinoma. Considering the previously conducted PCNL surgery and the diagnosis, it is proposed that the recurrent waist tumor originated from renal cell carcinoma (RCC), also termed renal adenocarcinoma. However, no evidence of the original RCC tumor was identified. Therefore, the selection of an effective treatment strategy was challenging.
doi:10.3892/ol.2015.3175
PMCID: PMC4487090  PMID: 26171018
percutaneous nephrolithotomy; renal cell carcinoma; waist tumor
14.  Reduced ubiquitin-specific protease 9X expression induced by RNA interference inhibits the bioactivity of hepatocellular carcinoma cells 
Oncology Letters  2015;10(1):268-272.
Ubiquitin-specific protease 9X (USP9X) is crucial in many tumor types, but not in hepatocellular carcinoma (HCC). The current study aimed to examine the effects of RNA interference on USP9X expression, and subsequently on the bioactivity of HCC SMMC7721 and HepG2 cells. The protein expression of USP9X in SMMC7721, HepG2 and normal human liver cell line L02 at the cellular level was determined by western blot analysis; USP9X was knocked down by small interfering RNA (siRNA) in HCC SMMC7721 and HepG2 cells. In vitro cell viability was assessed by MTT assay, apoptosis was determined by flow cytometry (FCM) and cell migration was evaluated by Transwell assays. The protein expression of USP9X in SMMC7721 and HepG2 were both significantly higher than that in L02 (P<0.01). The results of western blot demonstrated that the USP9X-siRNA could efficiently inhibit USP9X expression when compared with that of the negative control (NC) group (P<0.01) and MTT assay demonstrated that cell proliferation in USP9X-blocked cells was significantly reduced when compared with that of the NC group (P<0.01). The results of FCM revealed that apoptosis was significantly increased in USP9X-blocked cells when compared with that of the NC group (P<0.01). The results of transwell assay showed that cell migration was significantly inhibited in USP9X-blocked cells when compared with that of the NC group (P<0.01). These results show that expression of USP9X is upregulated in hepatoma cells SMMC7721 and HepG2, and that downregulating USP9X by siRNA may induce cell apoptosis, inhibit cell growth and cell migration in the HCC SMMC7721 and HepG2 cell lines. USP9X may therefore be a potential target for HCC treatment and early detection.
doi:10.3892/ol.2015.3152
PMCID: PMC4487130  PMID: 26171012
apoptosis; growth; hepatocellular carcinoma; migration; RNA interference; ubiquitin-specific protease 9X
15.  Comparison of the clinical value of multi-band mucosectomy versus endoscopic mucosal resection for the treatment of patients with early-stage esophageal cancer 
Oncology Letters  2015;9(6):2716-2720.
The present study aimed to compare the clinical value of multi-band mucosectomy (MBM) versus endoscopic mucosal resection (EMR) for the treatment of patients with early-stage esophageal cancer. Between January 2011 and December 2012, 68 patients with early-stage esophageal cancer who underwent MBM and EMR were enrolled into the present study. The curative resection rate, duration of surgery, complications and follow-up records were retrospectively analyzed. Of the 68 patients included, 33 were treated with MBM and 35 with EMR. There was no significant difference in the rate of complete resection between the MBM and EMR groups (P>0.05). The mean duration of surgery in the MBM group was statistically lower than that in the EMR group (P<0.05). There was no statistically significant difference in the intraoperative and post-operative complications between the MBM and EMR groups (P>0.05). Esophageal cancer reoccurred in 2 patients treated with MBM and 1 patient treated with EMR during the follow-up period (range, 3–24 months). Overall, MBM can be considered a better surgical option for the management of patients with early-stage esophageal cancer, as it offers higher histological curative resection rates and improved safety. However, further studies and a larger follow-up period are required to confirm the long-term curative effect.
doi:10.3892/ol.2015.3098
PMCID: PMC4473506  PMID: 26137134
multi-band mucosectomy; endoscopic mucosal resection; early-stage esophageal cancer
16.  Giant retroperitoneal bronchogenic cyst mimicking a cystic teratoma: A case report 
Oncology Letters  2015;9(6):2701-2705.
Retroperitoneal bronchogenic cysts (RBCs) are regarded as a rare type of congenital dysplasia disease that stems from the primitive foregut. Thus far, the exact pathogenesis of RBCs remains unknown. Due to an atypical clinical manifestation, RBCs are often incidentally detected and diagnosed by imaging modalities, such as computed tomography and magnetic resonance imaging. However, they are easily misdiagnosed due to their non-specific imaging features. Additionally, the most appropriate treatment strategy for an RBC is considered to be surgical resection. The present study reports the rare case of a 36-year-old female with a large RBC containing fatty fluid that was previously misdiagnosed as liposarcoma or cystic teratoma. Following a complex surgical resection, pathological findings confirmed a diagnosis of RBC. The follow-up examination showed that the patient was in good health at 16 months post-surgery, with no evidence of recurrence. Although rare, bronchogenic cysts must be considered in the differential diagnosis of retroperitoneal teratoma, and surgical resection should be pursued for symptom resolution and to establish a definitive histology.
doi:10.3892/ol.2015.3076
PMCID: PMC4473486  PMID: 26137131
retroperitoneal bronchogenic cyst; diagnostic imaging; therapeutics
17.  Ovarian cancer transformation from adenocarcinoma to undifferentiated small cell carcinoma: A case report 
Oncology Letters  2015;9(5):2230-2232.
The ovaries contain cells that have the capacity for regeneration and cancer stem cells (CSC) that are capable of differentiating aberrantly from the homeostatic controls. The histology of ovarian cancer does not usually change in a patient. However, CSCs are the origin of a number of tumors. CSCs are known to exist in ovarian carcinomas and the expression of CD44, c-Kit and CD133 has been identified in such carcinomas. This study presents the case of a patient diagnosed with ovarian cancer with an abdominal mass who underwent surgery, eight cycles of gemcitabine-paclitaxel chemotherapy and irradiation. Pathological examination indicated a transformation from adenocarcinoma to undifferentiated small cell carcinoma. The expression of CD133 changed from negative to positive in ovarian carcinomas. The present case indicates that any histological changes observed in ovarian neoplasms originate from neoplastic stem cells. In addition, this case demonstrates the importance of repeatedly assessing therapy by tumor biopsy throughout the course of ovarian cancer treatment.
doi:10.3892/ol.2015.3031
PMCID: PMC4467345  PMID: 26137046
ovarian cancer; adenocarcinoma; undifferentiated small cell carcinoma
18.  Clinical significance of pAkt and pErk1/2 expression in early-stage breast cancer patients treated with anthracycline-based adjuvant chemotherapy 
Oncology Letters  2015;9(4):1707-1714.
The expression of phosphorylated Akt (pAkt) and phosphorylated extracellular-regulated kinase 1/2 (pErk1/2) proteins may result in breast cancer progression and drug resistance in vitro, however, compelling evidence regarding the clinical significance of pAkt and pErk1/2 in early-stage breast cancer is currently lacking. Thus, the aim of the present study was to determine the prognostic value of pAkt and pErk1/2 expression in early-stage breast cancer patients treated with anthracycline-based adjuvant chemotherapy. Tumor specimens were obtained from 256 patients with early-stage breast cancer who had been treated with anthracycline-based adjuvant chemotherapy, and pAkt and pErk1/2 protein expression was immunohistochemically determined. The interactions between pAkt, pErk1/2 and clinical characteristics were assessed by performing χ2 tests, and survival functions were estimated using the Kaplan-Meier method. It was identified that pAkt and pErk1/2 were expressed in 38.7 and 33.6% of patients, respectively, and that pAkt protein expression was correlated with pErk1/2 protein expression (P<0.001). In addition, after a median follow-up period of 52.5 months, the patients with pAkt- and pErk1/2-negative tumors experienced a significantly longer disease-free survival (DFS) time compared with pAkt- or pErk1/2-positive patients (P=0.028). pErk1/2 expression was associated with the decreased DFS time of the patients (P=0.049), and pAkt and pErk1/2 expression were associated with the decreased DFS time in human epidermal growth factor receptor (HER2)-positive patients (P=0.002). pErk1/2 expression was associated with chemotherapy resistance (P=0.016). Thus, the coexpression of pAkt and pErk1/2 was an independent factor for a poor prognosis in early-stage and HER2-positive breast cancer patients. By contrast, pErk1/2 expression alone may be a poor predictor for determining the efficacy of anthracycline-based chemotherapy.
doi:10.3892/ol.2015.2965
PMCID: PMC4356398  PMID: 25789027
breast cancer; phosphorylated Akt; phosphorylated extracellular-regulated kinase 1/2; chemotherapy-resistance; prognosis
19.  Insufficient radiofrequency ablation promotes human hepatoma SMMC7721 cell proliferation by stimulating vascular endothelial growth factor overexpression 
Oncology Letters  2015;9(4):1893-1896.
The aims of the current study were to investigate the influence of insufficient radiofrequency ablation (RFA) on the cell proliferation of the human hepatocellular carcinoma (HCC) cells, SMMC7721, and to elucidate the underlying mechanism. SMMC7721 cells were subjected to a 47°C treatment regimen to simulate insufficient RFA, in the presence or absence of KN93 [a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII)], PD98059 [a specific inhibitor of extracellular signal-regulated kinase (ERK)], or axitinib (a specific inhibitor of vascular endothelial growth factor (VEGF) receptor]. Cell proliferation was determined using a thiazolyl terazolium assay (MTT). The levels of CaMKII, phospho-CaMKII, ERK, phospho-ERK and VEGF were observed by western blot analysis. The results demonstrated that the 47°C treatment regimen: i) Triggered upregulation of VEGF expression in the SMMC7721 cells, which was reduced by CaMKII or ERK inhibition; ii) induced ERK activation was prevented by KN93; and iii) promoted SMMC7721 cell proliferation, which was greatly inhibited by axitinib, KN93 and PD98059. In conclusion, the results indicated that insufficient RFA promotes SMMC7721 cell proliferation by activating CaMKII/ERK-dependent VEGF overexpression.
doi:10.3892/ol.2015.2966
PMCID: PMC4356410  PMID: 25789063
Ca2+/calmodulin-dependent protein kinase II; extracellular signal-regulated kinase; radiofrequency; SMMC7721
20.  Huaier aqueous extract induces apoptosis of human fibrosarcoma HT1080 cells through the mitochondrial pathway 
Oncology Letters  2015;9(4):1590-1596.
In recent years, aqueous extract of Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine, has been frequently used in China for complementary cancer therapy. However, the mechanisms underlying its anticancer effects have yet to be elucidated. The present study aimed to evaluate the ability of Huaier extract to inhibit proliferation, promote apoptosis and suppress mobility in the fibrosarcoma HT1080 cell line in vitro. The cells were treated with gradient doses of Huaier extract at concentrations of 0, 4, 8 or 16 mg/ml for 24, 48 or 72 h. The cell viability and motility were measured in vitro using MTT, invasive, migration and scratch assays. The distribution of the cell cycle and the extent of cellular apoptosis were analyzed by flow cytometry. The apoptotic pathways were detected using a mitochondrial membrane potential transition assay and western blotting. The results revealed that the cellular viability decreased significantly with increasing concentrations of Huaier extract. In addition, cell invasiveness and migration were also suppressed significantly. It was demonstrated that Huaier extract induced G2 cell-cycle arrest and cellular apoptosis in a time- and dose-dependent manner. The decreased mitochondrial membrane potential, the downregulation of B-cell lymphoma 2 and pro-caspase-3, and upregulation of Bcl-2-associated X protein, cleaved caspase-9 and caspase-3 suggested that Huaier extract induced the apoptosis of HT1080 cells through the mitochondrial pathway. The results of the present study indicate that Huaier extract is a potential complementary agent for the treatment of fibrosarcoma.
doi:10.3892/ol.2015.2906
PMCID: PMC4356327  PMID: 25789006
HT1080 cells; Huaier aqueous extract; apoptosis; mitochondrial pathway; cell motility
21.  Effect of hypoxia on hypoxia inducible factor-1α, insulin-like growth factor I and vascular endothelial growth factor expression in hepatocellular carcinoma HepG2 cells 
Oncology Letters  2015;9(3):1142-1148.
Hypoxic microenvironments and angiogenesis have been a focus of tumor research in previous years. The aim of the the present study was to create a hypoxic model and observe the effect of hypoxia on the expression of hypoxia inducible factor-1α (HIF-1α), insulin-like growth factor I (IGF-1) and vascular endothelial growth factor expression. The hypoxia model was generated using cobalt chloride (CoCl2) and an MTT assay was used to observe the influence of hypoxia on HepG2 cells. Reverse transcription-polymerase chain reaction, western blotting, ELISA and confocal immunofluorescence microscopy were used to detect the expression of HIF-1α, IGF-1 and VEGF in HepG2 cells, in which hypoxia was induced by various concentrations of CoCl2 and for various incubation times. The cell viability worsened with increasing concentrations of CoCl2. The expression of HIF-1α and IGF-1R was observed in hypoxic HepG2 cells, with the exception of HIF-1α mRNA. The expression of IGF-1R and VEGF mRNA and protein was correlated with the concentration of CoCl2 and the time that hypoxia was induced for. The expression of HIF-1α mRNA and protein was positively correlated with the expression of the VEGF mRNA and protein in a dose- and time-dependent manner under hypoxic conditions. Using immunofluorescence, it was observed that IGF-1R and HIF-1α were secreted from the hypoxic HepG2 cells. It was concluded that hypoxia induces the accumulation of IGF-1R and HIF-1α mRNA and protein, which regulates the expression of VEGF mRNA and protein in hypoxic HepG2 cells.
doi:10.3892/ol.2015.2879
PMCID: PMC4315007  PMID: 25663870
hepatocellular carcinoma; hypoxia; hypoxia inducible factor-1α; insulin-like growth factor I; vascular endothelial growth factor
22.  Impact of obesity upon prostate cancer-associated mortality: A meta-analysis of 17 cohort studies 
Oncology Letters  2014;9(3):1307-1312.
A number of epidemiological studies have suggested that obesity is associated, albeit inconsistently, with the incidence of prostate cancer (PCa). In order to provide a quantitative assessment of this association, the present study examined the correlation between obesity and the incidence and associated mortalities of PCa in an updated meta-analysis of cohort studies. The cohort studies were identified by searching the EMBASE and MEDLINE databases on January 1, 2014. The summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. In total, 17 studies, which included 3,569,926 individuals overall, were selected according to predefined inclusion criteria. Based upon the results of the random-effects models, obesity was not significantly correlated with the incidence of PCa (RR, 1.00; 95% CI, 0.95–1.06). However, further analysis revealed that obesity was significantly correlated with an increased risk of aggressive PCa (RR, 1.14; 95% CI, 1.04–1.25). Furthermore, an increased risk of PCa-associated mortality was significantly associated with obesity (RR, 1.24; 95% CI, 1.15–2.33), without any heterogeneity between the studies (I2=0.0%; P=0.847). The present study provides preliminary evidence to demonstrate that obesity is a significant risk factor for aggressive PCa and PCa-specific mortality. The low survival rates observed among obese males with PCa may be a likely explanation for this association.
doi:10.3892/ol.2014.2841
PMCID: PMC4315023  PMID: 25663903
prostate cancer; obesity; prospective cohort studies; incidence; mortality; meta-analysis
23.  T-cell acute lymphoid leukemia resembling Burkitt leukemia cell morphology: A case report 
Oncology Letters  2014;9(3):1236-1238.
Biphenotypic acute leukemia (BAL) is an uncommon type of cancer, which accounts for <5% of all adult ALs. Based upon a previously described scoring system, the European Group for the Immunological Classification of Leukemias (EGIL) proposed a set of diagnostic criteria for BAL. This scoring system is based upon the number and degree of specificity of several markers for myeloid or T/B-lymphoid blasts. The present study describes a case of T-cell acute lymphoblastic leukemia (T-ALL) with Burkitt-like cytology, which according to the French-American-British classification, corresponded to a diagnosis of Burkitt type L3 ALL. Flow cytometry analysis demonstrated that the blasts were positive for T-lymphoid markers, cytoplasmic cluster of differentiation (CD)3, CD7 and CD56, and myeloid markers, CD13, CD33 and CD15. At first, a diagnosis of BAL was suggested by the EGIL score, however, according to the 2008 World Health Organization criteria, a case of T-ALL with aberrant myeloid markers was established. The study also reviewed the literature and discussed the limitations of the EGIL scoring system in clinical decision making, to aid in the selection of an appropriate therapeutic regimen.
doi:10.3892/ol.2014.2825
PMCID: PMC4314994  PMID: 25663889
biphenotypic acute leukemia; acute lymphoblastic leukemia; Burkitt leukemia
24.  Extraskeletal Ewing’s sarcoma/primitive neuroectodermal tumor of the mediastinum: Significant response to chemoradiotherapy 
Oncology Letters  2014;9(2):626-628.
Primary mediastinal extraskeletal Ewing’s sarcoma (EES) is quite rare. To the best of our knowledge, only five cases have been reported. Given the paucity of data, there is consequently no optimal treatment strategy available. The current study presents the case of a 51-year-old female with unresectable EES of the posterior mediastinum. Chemoradiotherapy achieved near complete remission without severe side-effects. The literature associated with EES is also reviewed. The present case highlights the possibility of the diagnosis of EES for a mediastinal mass. Chemoradiotherapy may be a good option for unresectable cases. In the future, large-scale collaborative clinical trials should be initiated to provide an improved understanding of the characteristics of EES and the best treatment strategy.
doi:10.3892/ol.2014.2788
PMCID: PMC4301504  PMID: 25621030
extraskeletal Ewing’s sarcoma; mediastinum; chemoradiotherapy
25.  MicroRNA-133a suppresses colorectal cancer cell invasion by targeting Fascin1 
Oncology Letters  2014;9(2):869-874.
MicroRNAs (miRs) are a type of small non-coding RNA molecule that are involved in gene silencing and the regulation of cancer progression; miR-133a in particular has been implicated in colorectal cancer, although its specific role and underlying mechanism have yet to be determined. In the present study, the expression level of miR-133a was significantly downregulated in a number of colorectal cancer cell lines, as well as in colorectal cancer tissues compared with the normal adjacent tissues. Furthermore, the Fascin1 (FSCN1) gene was identified as a direct target of miR-133a, and the protein expression level of FSCN1 was negatively regulated by miR-133a in colorectal cancer cells. Additionally, restoration of miR-133a expression and downregulation of FSCN1 protein expression suppressed colorectal cancer cell invasion, while overexpression of FSCN1 reversed the inhibitory effect of miR-133a upregulation on colorectal cancer cell invasion. Thus, the present data indicates that miR-133a may at least partially suppress colorectal cancer cell invasion, possibly via the inhibition of FSCN1 expression. The present study highlights the important role of miR-133a in the progression of colorectal cancer.
doi:10.3892/ol.2014.2753
PMCID: PMC4301513  PMID: 25621061
colorectal cancer; microRNA-133a; Fascin1; invasion

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