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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.
PMCID: PMC4049741  PMID: 24932248
bone marrow mesenchymal stem cell; autotransplantation; diabetes mellitus; skin defect; tumorigenicity
2.  Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death 
Oncology Letters  2016;12(5):3403-3410.
Renal cell carcinoma (RCC) is resistant to standard radiotherapy. Ubenimex, an aminopeptidase N inhibitor, is widely used as an adjunct therapy after surgery to enhance the function of immunocompetent cells and confer antitumor effects. Our previous study demonstrated that ubenimex induces autophagic cell death in RCC cells. Recently, the molecular mechanism of autophagy induction has been associated with radiosensitivity in RCC cells. In the present study, the ability of ubenimex to enhance RCC cell sensitivity to radiation via the induction of autophagic cell death was determined, and the mechanism of action of this effect was investigated. The 786-O and OS-RC-2 human RCC cell lines were treated with 0.5 mg/ml ubenimex and different doses of irradiation (IR). The cell viability was measured using a colony-formation assay and flow cytometry. Acridine orange (AO)-ethidium bromide (EB) staining was assessed by fluorescence microscopy as an indicator of autophagic cell death. Protein expression was assessed by western blotting. Autophagosomes were evaluated using transmission electron microscopy. RCC cells were used to evaluate the sensitivity to radiation using clonogenic survival and lactate dehydrogenase assays. Furthermore, these parameters were also tested at physiological oxygen levels. The AO-EB staining and flow cytometry of the OS-RC-2 cells indicated that the combined treatment significantly enhanced autophagic cell death compared with ubenimex or IR alone. Therefore, treatment with ubenimex did not significantly alter cell cycle progression but increased cell death when combined with radiation. An Akt agonist could significantly weaken this effect, indicating that ubenimex may act as an Akt inhibitor. Furthermore, the western blot analysis indicated that the combined treatment inhibited the Akt signaling pathway compared with ubenimex treatment or IR alone. Ubenimex may enhance RCC cell sensitivity to radiation by inducing cell autophagy. This induction changes the role of autophagy from protective to lethal in vitro, and this switch is associated with the inhibition of the Akt signaling pathway.
PMCID: PMC5103958  PMID: 27900012
ubenimex; radiosensitivity; RCC; autophagic cell death; Akt
3.  Giant malignant phyllodes tumor of the breast: A rare case report and literature review 
Oncology Letters  2016;12(1):121-124.
Malignant phyllodes tumor of the breast (MPTB) is rarely encountered in clinical practice. Preoperative diagnosis is challenging due to nonspecific radiological and histological features, and the prognostic factors and optimal treatment remain controversial. The current report describes the case of a middle-aged female with giant MPTB who underwent multidisciplinary intervention, including surgery, postoperative chemotherapy and radiotherapy. To date, the disease-free survival (DFS) of the patient has reached 18 months. Furthermore, a related literature review summarize the clinicopathological characteristics and treatment progress regarding MPTB is presented, along with an analysis of the indications for therapeutic strategy in the current case. In the future, multi-center clinical trials must be initiated to identify the criteria for diagnosis and optimal treatment consensus for MPTB. In conclusion, the present case highlights that multidisciplinary management may contribute to DFS following the treatment of giant MPTB.
PMCID: PMC4906910  PMID: 27347111
malignant phyllodes tumor; breast; radiotherapy
4.  Significance of ETV6 rearrangement in acute promyelocytic leukemia with t(15;17)/promyelocytic leukemia/retinoic acid receptor alpha 
Oncology Letters  2016;11(6):3953-3960.
Acute promyelocytic leukemia (APL) is a common subtype of acute myeloid leukemia in China. Since the application of arsenic trioxide and all-trans retinoic acid in the treatment of APL, the prognosis has greatly improved. However, ~20% of patients with APL relapse upon completing chemotherapy. Decreasing the relapse rate and incidence of early mortality may pose the greatest challenges for the future management of APL. Recently, Ets variant 6 (ETV6) was reported to be involved in a variety of translocations associated with hematological malignancies of myeloid and lymphoid origin. To date, little is known about the clinical implication of ETV6 rearrangement in APL. In the present study, ETV6 rearrangement was examined by split-signal fluorescence in situ hybridization in 258 adults with APL, and its association with the clinical features and outcomes of the patients was analyzed. The data suggested that ETV6 rearrangement may be an independent unfavorable prognostic factor for overall survival in APL patients.
PMCID: PMC4888070  PMID: 27313723
acute promyelocytic leukemia; Ets variant 6 gene; split-signal FISH; rearrangement; prognosis
5.  MiR-593 mediates curcumin-induced radiosensitization of nasopharyngeal carcinoma cells via MDR1 
Oncology Letters  2016;11(6):3729-3734.
Curcumin (Cur) exhibits radiosensitization effects to a variety of malignant tumors. The present study investigates the radiosensitizing effect of Cur on nasopharyngeal carcinoma (NPC) cells and whether its mechanism is associated with microRNA-593 (miR-593) and multidrug resistance gene 1 (MDR1). A clonogenic assay was performed to measure the radiosensitizing effect. The expression of miR-593 and MDR1 was analyzed by quantitative polymerase chain reaction (qPCR) or western blot assay. A transplanted tumor model was established to identify the radiosensitizing effect in vivo. A luciferase-based reporter was constructed to evaluate the effect of direct binding of miR-593 to the putative target site on the 3′ UTR of MDR1. The clonogenic assay showed that Cur enhanced the radiosensitivity of cells. Cur (100 mg/kg) combined with 4 Gy irradiation inhibited the growth of a transplanted tumor model in vivo, resulting in the higher inhibition ratio compared with the radiotherapy-alone group. These results demonstrated that Cur had a radiosensitizing effect on NPC cells in vivo and in vitro; Cur-mediated upregulation of miR-593 resulted in reduced MDR1 expression, which may promote radiosensitivity of NPC cells.
PMCID: PMC4888061  PMID: 27313684
radiosensitization; curcumin; multidrug resistance gene 1; microRNA-593; nasopharyngeal carcinoma
6.  Synchronous occurrence of gastrointestinal stromal tumor and acute myeloid leukemia: A case report and review of the literature 
Oncology Letters  2016;11(5):2977-2980.
Gastrointestinal stromal tumors (GISTs) originate from the mesenchymal tissue of the gastrointestinal tract. The pathogenesis of GIST is associated with the mutational activation of the receptor tyrosine kinase cluster of differentiation (CD)117 or platelet-derived growth factor receptor-α. Overall, ~60% of GISTs occur in the stomach. Clinically, GISTs may coexist with various types of cancer, including liver cancer, pancreatic tumors and lymphoma, either synchronously or metachronously. The present study reports the case of a patient with the synchronous occurrence of a CD117-positive GIST and acute myeloid leukemia. A 69-year-old man was hospitalized for heart palpitations and dizziness, and was diagnosed with acute myeloid leukemia (AML) by bone marrow aspiration and flow cytometry analysis. An abdominal computed tomograpy and gastroscopy revealed the presence of GIST. The patient received chemotherapy in combination with imatinib (400 mg/day), and the mass was removed 2 months later. To the best of our knowledge, the present study is the first reported case of the synchronous development of a CD117-positive GIST and AML. Additional studies are required in order to understand the association between GIST and hematological malignancies.
PMCID: PMC4840780  PMID: 27123049
gastrointestinal stromal tumor; acute myeloid leukemia; cluster of differentiation 117; cluster of differentiation 34
7.  Functional mechanism of the enhancement of 5-fluorouracil sensitivity by TUSC4 in colon cancer cells 
Oncology Letters  2015;10(6):3682-3688.
5-Fluorouracil (5-FU) is the chemotherapeutic drug of choice for the treatment of metastatic colorectal cancer (CRC). Tumor suppressor candidate 4 (TUSC4), also referred to as nitrogen permease regulator-like 2 (NPRL2), is located at chromosome 3p21.3 and expressed in numerous normal tissues, including the heart, liver, skeletal muscle, kidney, and pancreas. The aim of the present study was to investigate the functional mechanism by which TUSC4 affects sensitivity to 5-FU and to determine its clinical significance in CRC. The results of the present study demonstrated that TUSC4 overexpression increases the sensitivity of HCT116 cells to 5-FU. The IC50 of 5-FU was reduced in cells transduced with TUSC4 compared with negative control (NC) cells, and the effect of TUSC4 on 5-FU sensitivity was time dependent. Following TUSC4 transduction in HCT116 cells, a proportion of the cells were arrested in the G1 phase of the cell cycle, and a reduction in the S phase population was observed. Flow cytometry analysis revealed that TUSC4 transduction and 5-FU treatment increased apoptosis compared with NC cells. The mechanism through which TUSC4 overexpression enhances 5-FU sensitivity involves the downregulation of the function of the PI3K/Akt/mTOR network. Furthermore, 5-FU upregulated caspase-3 and caspase-9, promoting apoptosis in TUSC4-overexpressing cells compared with cells that were transduced with TUSC4 or treated with 5-FU and NC cells. The findings of the present study indicate that TUSC4 has potential as a biomarker for the prediction of the response to 5-FU and prognosis in patients with colorectal cancer and other types of human cancer. TUSC4 may also act as a molecular therapeutic agent for enhancing the patient's response to 5-FU treatment.
PMCID: PMC4665636  PMID: 26788191
TUSC4; colorectal cancer; PI3K/Akt/mTOR; 5-fluorouracil
8.  Low expression of spindle checkpoint protein, Cenp-E, causes numerical chromosomal abnormalities in HepG-2 human hepatoma cells 
Oncology Letters  2015;10(5):2699-2704.
The aim of the present study was to investigate the expression, localization and role of centromere-associated protein E (Cenp-E) in hepatoma cells. The Cenp-E mRNA expression levels in the HepG-2 human hepatocellular carcinoma and LO2 normal hepatic cell lines following treatment with nocodazole were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Furthermore, the localization and expression of Cenp-E protein in the two cell types was visualized using indirect immunofluorescence. RT-qPCR was also performed to detect the Cenp-E mRNA expression levels in LO2 cells before and after RNA interference. Additional evaluation of the function of interfered cells was performed using indirect immunofluorescence. The results of RT-qPCR demonstrated that the protein expression levels of Cenp-E in the two cell lines prior to treatment with nocodazole were not significantly different (P>0.05). However, the upregulation of Cenp-E expression levels in the LO2 cells was significantly higher compared with that in the HepG-2 cells during cell division (P<0.05). Indirect immunofluorescence analysis indicated that the Cenp-E protein was predominantly located in the nucleus, and that Cenp-E protein expression in nuclei with abnormal mitosis was markedly lower compared with that in nuclei exhibiting normal mitosis. Indirect immunofluorescence also determined that the ratio of dyskaryosis was significantly higher in cells that had undergone Cenp-E interference compared with normal cells. Thus, the present study indicated that the low expression of Cenp-E mRNA may be an important reason for numerical chromosomal abnormalities in human hepatoma cells.
PMCID: PMC4665365  PMID: 26722229
centromere-associated protein E; chromosome numerical abnormality; hepatoma; spindle checkpoint protein
9.  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.
PMCID: PMC4487161  PMID: 26171025
gastric cancer; microRNA; clinical pathology
10.  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.
PMCID: PMC4246631  PMID: 25436015
gastric cancer; intraperitoneal chemotherapy; dual chemotherapy; docetaxel; cisplatin; fluorouracil
11.  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.
PMCID: PMC4214449  PMID: 25364456
cytokine-induced killer cells; immunotherapy; adoptive; allogeneic; malignant tumor; carcinoma; non-small cell lung
12.  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.
PMCID: PMC4186625  PMID: 25295080
cutaneous flaps; foot and ankle; malignant melanoma; salvage surgery; soft tissue defects
13.  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.
PMCID: PMC4156168  PMID: 25202367
CXC chemokine receptor 4; RNA interference; breast cancer
14.  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.
PMCID: PMC4049698  PMID: 24932256
cisplatin; radiosensitivity; synergistic killing; lung cancer; autophagy; apoptosis
15.  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.
PMCID: PMC3961442  PMID: 24944689
rat S100A4; functional expression; gene recombination
16.  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.
PMCID: PMC3796425  PMID: 24137432
human gastric cancer; cancer stem cell; OCT4; ABCG2
17.  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.
PMCID: PMC3389651  PMID: 22783399
renal cell carcinoma; CCN3; migration; tumorigenicity
18.  Quantitative contrast-enhanced ultrasonography for the differential diagnosis of endometrial hyperplasia and endometrial neoplasms 
Oncology Letters  2016;12(5):3763-3770.
The present study aimed to investigate the feasibility of applying contrast-enhanced ultrasonography (CEUS) imaging technology for distinguishing between benign and malignant endometrial lesions, and to screen markers that could be correlated with the pathological results. In this study, endometrial diseases were diagnosed by biopsy under hysteroscopy and CEUS examinations. The intensity and time parameters of the time-intensity curve (TIC) were analyzed. The mean arrival time (AT), time-to-peak (TTP), rise time (RT), washout half-time and clearance half-time of malignant lesions were shorter than those of benign lesions (P<0.05), whereas the average peak intensity (PI) and enhancement intensity (EI) of malignant lesions were higher than those of benign lesions (P<0.05). The receiver operating characteristic curve showed the following cut-off values: PI, 29.2 dB; EI, 21.35 dB; AT, 12.75 sec; TTP, 26.75 sec; RT, 13.2 sec; clearance half-time, 89.3 sec; and washout half-time, 75.45 sec. The lesions with PI, an EI higher than that of the cut-off and lesions with an AT, TTP, RT, half clearing time and washout half-time shorter than the cut-off were considered malignant. The TTP, RT and half clearing time were negatively correlated with microvessel density (MVD), i.e., MVD was higher when the TTP, RT and half clearing time were shorter. Overall, changes in the enhancement and clearing of lesions could be quantitatively analyzed by CEUS TIC and further discriminate benign from malignant lesions. In the present study, CEUS appeared to indirectly reflect blood vessel changes inside the lesions and provided a pre-operative non-invasive fast imaging method for the diagnosis of endometrial disease.
PMCID: PMC5104163  PMID: 27895728
contrast-enhanced ultrasound; time-intensity curve; benign; malignant; endometrium
19.  High PARP-1 expression is associated with tumor invasion and poor prognosis in gastric cancer 
Oncology Letters  2016;12(5):3825-3835.
Poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1) was previously demonstrated to be overexpressed in numerous malignant tumors and associated with invasiveness and poor prognosis. However, the expression of the PARP-1 protein in gastric cancer and its association with clinical outcomes requires further investigation. In the present study, the expression of PARP-1 in 564 gastric cancer tissues and 335 tumor-adjacent control tissues is investigated, using tissue microarray-based immunohistochemistry. PARP-1 expression levels were demonstrated to be significantly higher in gastric cancer tissue samples, as compared with control tissue samples. In gastric cancer, high PARP-1 expression levels were significantly associated with Helicobacter pylori (H. pylori) infection (P=0.032), decreased differentiation (P<0.001), increased depth of invasion (P=0.037), presence of lymphatic invasion (P<0.001), presence of lymph node metastasis (P<0.001), and advanced tumor-node-metastasis (TNM) stage (P=0.015). High PARP-1 expression levels were associated with a significantly shorter overall survival rate (P<0.001) and disease-free survival rate (P=0.001) in patients with gastric cancer, particularly a subset of patients with H. pylori infection or an advanced TNM stage. In addition, univariate analysis indicated that PARP-1 high expression levels were significantly associated with a poor prognosis in gastric cancer. These results suggest that PARP-1 expression may be involved in the progression and prognosis of gastric cancer, particularly H. pylori-positive or advanced-stage gastric cancer.
PMCID: PMC5104177  PMID: 27895737
gastric cancer; poly (adenosine diphosphate-ribose) polymerase 1; H. pylori infection; metastasis; prognosis
20.  BCAT1 promotes tumor cell migration and invasion in hepatocellular carcinoma 
Oncology Letters  2016;12(4):2648-2656.
Branched-chain amino acid transaminase 1 (BCAT1) has been associated with numerous types of tumors; however, few previous studies have evaluated the expression and role of BCAT1 in hepatocellular carcinoma (HCC). In the present study, the expression of BCAT1 was detected by reverse transcription-quantitative polymerase chain reaction and immunoblotting in six HCC cell lines and 74 pairs of HCC and adjacent non-cancerous liver tissues. In addition, the correlation between the expression levels of c-Myc and BCAT1 was analyzed using immunohistochemistry. Furthermore, RNA silencing was performed using c-Myc-specific or BCAT1-specific small interfering RNA, after which wound healing and Transwell cell invasion assays were performed. Finally, the clinicopathological characteristics of BCAT1 in patients with HCC were analyzed. It was shown that the expression of BCAT1 was significantly higher in HCC tissues compared with adjacent non-tumor tissues (P<0.001), and in HCC cell lines compared within the L-02 hepatic cell line (P<0.001). In addition, immunohistochemical analyses indicated that the expression of BCAT1 was positively correlated with c-Myc (r=0.706, P<0.001). BCAT1 expression was shown to be downregulated in c-Myc-knockdown cells, and silencing of BCAT1 expression reduced the invasion and migration of HCC cells. Furthermore, a clinical analysis indicated that BCAT1 expression in HCC tissues was significantly associated with the tumor-node-metastasis stage, tumor number and tumor differentiation (all P<0.05), and that BCAT1 was able to predict the 5-year survival and disease-free survival rates of patients with HCC (both P<0.001). The results of the present study suggested that BCAT1 expression is upregulated in patients with HCC, and that BCAT1 may serve as a potential molecular target for the diagnosis and treatment of HCC.
PMCID: PMC5038498  PMID: 27698837
branched-chain amino acid transaminase 1; hepatocellular carcinoma; prognostic factor; c-Myc
21.  Cisplatin-resistant osteosarcoma cells possess cancer stem cell properties in a mouse model 
Oncology Letters  2016;12(4):2599-2605.
Osteosarcoma is the most common malignancy of the bones, and although advances in chemotherapy and surgery had been achieved in recent years, the long-term survival rate has reached a plateau. The main reason for this is the aggressive malignant potential and poor response of the disease to chemotherapy. However, several studies have found that tumor resistance is associated with cancer stem cells (CSCs). To address this issue, in the present study, osteosarcoma cells were treated with specially designated concentrations of cisplatin (CDDP) in a mouse model. Hematoxylin and eosin staining analyses were performed to assess tissue structure, in vivo passaging and CDDP treatment. Drug resistance genes and well-established stemness genes were detected by quantitative polymerase chain reaction. A serum-starved sphere formation assay was adopted to evaluate the ability to generate spherical clones and flow cytometry as used to test the expression of the cluster of differentiation 117 and Stro-1 surface markers, known as markers of CSCs. It was found that CDDP could induce an effect of resistance in the osteosarcoma cells, which possessed cancer stem CSC properties, as shown by the elevated expression of CSC marker genes and the higher expression of the cluster of differentiation 117 and Stro-1 surface markers. Moreover, the cells that dissociated from the tumor tissues exhibited an increased ability to form sarcospheres. The results of this study provided a significant correlation between resistance and CSCs, and revealed a clue indicating that osteosarcoma recurrence is likely to be associated with CSCs.
PMCID: PMC5038486  PMID: 27698833
osteosarcoma; cisplatin; cancer stem cells; resistant
22.  4-HPR impairs bladder cancer cell migration and invasion by interfering with the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways 
Oncology Letters  2016;12(3):1833-1839.
In order to identify the anti-invasive and anti-metastatic effect of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on the human bladder cancer EJ cell line, and to study its impact on the expression of wingless-type mouse mammary tumor virus integration site family, member 5a (Wnt5a), the phosphorylation of c-Jun N-terminal kinase (JNK), the expression levels of matrix metalloproteinase-2 (MMP-2), and the migration and invasion of EJ cells, migration and Matrigel invasion assays, as well as western blot analyses, were used in the present study. The results of the migration and Matrigel invasion assays indicated that the inhibitor of JNK SP600125 could inhibit the effect of 4-HPR on EJ cells. The expression of Wnt5a and MMP-2, and the phosphorylation of JNK, were analyzed by western blotting. The data revealed that 4-HPR inhibited the migration and invasion of bladder cancer cells through stimulating Wnt5a activation, causing the downregulation of MMP-2 expression and enhancing the phosphorylation of JNK in these cells. However, JNK signaling did not appear to have a direct effect on the expression of MMP-2. The present study demonstrated that 4-HPR may be a potent anti-invasive and anti-metastatic agent that functions via the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways.
PMCID: PMC4998198  PMID: 27602114
4-HPR; Wnt5a; JNK; MMP-2; migration and invasion; bladder cancer
23.  Expression of microRNA-30a-5p in drug-resistant and drug-sensitive ovarian cancer cell lines 
Oncology Letters  2016;12(3):2065-2070.
The present study aimed to explore the expression of microRNA (miRNA or miR) in drug-resistant and drug-sensitive ovarian cancer cell lines, and to seek the potential therapeutic target of ovarian cancer drug-resistant mechanism in order to improve drug resistance by altering miRNA levels. The drug-resistant characteristics of SKOV3/DDP, SKOV3, COC1/DDP and COC1 cell lines were studied. The miRNAs that were differentially expressed between cisplatin-resistant cells and its parental cells in ovarian cancer were screened with a miRNA chip. The effect of miRNAs was detected, and their drug-resistant mechanism was investigated by transfection and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide methods. Among the expression screening of miRNAs, 41 mRNAs, including Homo sapiens (hsa)-miR-30a-5p and hsa-miR-34c-5p, were highly expressed in the drug-resistant cells, whereas 44 miRNAs, including hsa-miR-96-5p and hsa-miR-200c-3p, were lowly expressed. The expression levels of hsa-miR-30a-5p in two types of ovarian cancer chemotherapy-resistant cell lines were significantly higher than those in chemotherapy-sensitive cell lines, which was associated with ovarian cancer chemotherapy resistance. In conclusion, high expression of miRNA-30a-5p was able to promote cell growth and colony forming ability, and enhance cell migration and invasion. Thus, miRNA-30a-5p is expected to become a meaningful novel target for ovarian cancer resistant treatment.
PMCID: PMC4998657  PMID: 27602140
ovarian cancer; microRNA; microRNA-30a-5p; drug resistance
24.  A novel method to limit breast cancer stem cells in states of quiescence, proliferation or differentiation: Use of gel stress in combination with stem cell growth factors 
Oncology Letters  2016;12(2):1355-1360.
The majority of cancer stem cells exist in the G0, or quiescent phase of the cell cycle. However, the cells can escape quiescence following routine radiotherapy and chemotherapy, resulting in tumor recurrence. Presently, achieving the accurate regulation of cancer stem cell growth in order to study a specific state, including the quiescent (mostly G0 or G1 phase), proliferative (mostly S phase) or differential (mostly G2/M phase) states, can be challenging. This makes the determination of cell cycle state-specific characteristics and analysis of potential intervention treatments difficult, particularly for quiescent cells. Breast cancer stem cells were cultured on a soft or hard agar matrix surface in the presence or absence of stem cell growth factors. Cells could be successfully limited in either the quiescent, proliferative or differentiated states. These findings provide a foundation for further study of the cell cycle in breast cancer stem cells.
PMCID: PMC4950051  PMID: 27446437
breast cancer; cell cycle; growth factor; tumor stem cells
25.  Identification of key target genes and pathways in laryngeal carcinoma 
Oncology Letters  2016;12(2):1279-1286.
The purpose of the present study was to screen the key genes associated with laryngeal carcinoma and to investigate the molecular mechanism of laryngeal carcinoma progression. The gene expression profile of GSE10935 [Gene Expression Omnibus (GEO) accession number], including 12 specimens from laryngeal papillomas and 12 specimens from normal laryngeal epithelia controls, was downloaded from the GEO database. Differentially expressed genes (DEGs) were screened in laryngeal papillomas compared with normal controls using Limma package in R language, followed by Gene Ontology (GO) enrichment analysis and pathway enrichment analysis. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed using Cytoscape software and modules were analyzed using MCODE plugin from the PPI network. Furthermore, significant biological pathway regions (sub-pathway) were identified by using iSubpathwayMiner analysis. A total of 67 DEGs were identified, including 27 up-regulated genes and 40 down-regulated genes and they were involved in different GO terms and pathways. PPI network analysis revealed that Ras association (RalGDS/AF-6) domain family member 1 (RASSF1) was a hub protein. The sub-pathway analysis identified 9 significantly enriched sub-pathways, including glycolysis/gluconeogenesis and nitrogen metabolism. Genes such as phosphoglycerate kinase 1 (PGK1), carbonic anhydrase II (CA2), and carbonic anhydrase XII (CA12) whose node degrees were >10 were identified in the disease risk sub-pathway. Genes in the sub-pathway, such as RASSF1, PGK1, CA2 and CA12 were presumed to serve critical roles in laryngeal carcinoma. The present study identified DEGs and their sub-pathways in the disease, which may serve as potential targets for treatment of laryngeal carcinoma.
PMCID: PMC4950495  PMID: 27446427
laryngeal cancer; differentially expressed genes; protein-protein interaction network; sub-pathway analysis

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