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DDR1 promotes breast tumor growth by suppressing antitumor immunity

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Breast cancer is the second leading cause of cancer-associated mortality among women worldwide. Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and is defined by its aggressive nature and limited treatment options. Therefore, there is an urgent need to develop effective therapies for TNBC in order to improve breast cancer outcomes, as targeted therapies have done in other subtypes of breast cancer. Discoidin domain receptor tyrosine kinase 1 (DDR1) is activated by collagens, which are important components of the tumor stroma; therefore, DDR1 may serve a critical role in the communication between tumor cells and the tumor microenvironment. The aim of the present study was to determine how tumor DDR1 regulated tumor growth by affecting tumor infiltrated T cells. First, the DDR1 expression levels from a cohort of patients with breast cancer were analyzed. The results revealed that there were higher levels of DDR1 expression in tumor tissues compared with adjacent normal tissues. Overexpression of DDR1 in 4T1 cells promoted tumor growth in vivo, while knockout of DDR1 in EMT6 cells decreased tumor growth in vivo. In addition, it was revealed that DDR1 regulated tumor growth by modulating tumor infiltrating T cells, CD4(+) and CD8(+). Furthermore, inhibition of DDR1 by neutralizing antibodies decreased breast cancer growth in vivo. To the best of our knowledge, the results of the present study demonstrated for the first time that DDR1 expressed on the tumor cells promoted breast tumor growth by suppressing antitumor immunity. The present findings indicated that DDR1 may not only have a critical role in the progression of breast cancer, but may also serve as a potential therapeutic target for breast cancer, particularly TNBC.

JIF:3.04

Potential role for second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia harboring additional clonal chromosome abnormalities: A retrospective CML Cooperative Study Group analysis

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Tyrosine kinase inhibitor (TKI) treatment is the standard of care for patients with chronic myeloid leukemia (CML). Even in the imatinib era, the presence of 'clonal chromosomal abnormalities' in the Philadelphia chromosome (CCA/Ph+) at diagnosis reportedly increased the risk of disease progression and predicted shorter survival. However, it remains unclear whether CCA/Ph+ is a poor prognostic marker in the era of new-generation TKIs. The data of patients with CML in the chronic phase (CP) that were extracted from the CML Cooperative Study Group database were retrospectively analyzed. Of the 328 eligible patients, 33 (10.1%) had CCA/Ph+, including 9 major route and 24 minor route aberrations. The characteristics of patients with and without CCA/Ph+ were similar; however, the proportion of blasts was higher among patients with CCA/Ph+. Notably, the survival rate of patients with CCA/Ph+ was not inferior to that of patients without CCA/Ph+, and there were no differences in responses to TKIs. All 9 patients with major route CCA/Ph+ attained a major molecular response (MMR) with no disease progression, and 8 ultimately achieved a deep molecular response. In particular, the median interval between TKI initiation and achievement of MMR was shorter in patients initially treated with a second-generation TKI than in those treated with imatinib (5 vs. 10 months). The present retrospective study, thus, revealed favorable treatment outcomes in CML-CP patients with CCA/Ph+ treated with second-generation TKIs. The data indicated that administering second-generation TKIs as first-line treatments is preferable in CML-CP patients with CCA/Ph+.

JIF:3.04

Establishment and characterization of a mouse tumor cell line with irreversible downregulation of MHC class I molecules

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

In the majority of human tumors, downregulation of major histocompatibility complex class I (MHC-I) expression contributes to the escape from the host immune system and resistance to immunotherapy. Relevant animal models are therefore needed to enhance the efficacy of cancer immunotherapy. As loss of beta-2 microglobulin expression results in irreversible downregulation of surface MHC-I molecules in various human tumors, the beta-2 microglobulin gene (B2m) was deactivated in a mouse oncogenic TC-1 cell line and a TC-1/dB2m cell line that was negative for surface MHC-I expression was derived. Following stimulation with interferon gamma, MHC-I heavy chains, particularly the H-2D(b) molecules, were found to be expressed at low levels on the cell surface, but without beta-2 microglobulin. B2m deactivation in TC-1/dB2m cells led to reduced proliferation and tumor growth. These cells were insensitive to DNA vaccination and only weakly responsive to combined immunotherapy with a DNA vaccine and the ODN1826 adjuvant. In vivo depletion demonstrated that NK1.1(+) cells were involved in both reduced tumor growth and an antitumor effect of immunotherapy. The number of immune cells infiltrating TC-1/dB2m-induced tumors was comparable with that in tumors developing from TC-1/A9 cells characterized by reversible MHC-I downregulation. However, the composition of the cell infiltrate was different and, most importantly, infiltration with immune cells was not increased in TC-1/dB2m tumors after immunotherapy. Therefore, the TC-1/dB2m cell line represents a clinically relevant tumor model that may be used for enhancement of cancer immunotherapy.

JIF:3.04

Olive tree blossom polyphenolic extracts exert antioxidant and antimutagenic activities in vitro and in various cell lines

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Olive oil has held a prominent place in the Mediterranean diet since ancient times due to its beneficial effects on human health thus, becoming the subject of great scientific interest. Although numerous studies have examined the biological action of olive and olive oil extracts, the literature lacks studies investigating the putative antioxidant capacity of olive tree flower extracts. Given that olive tree flowers are actually by-products of the olive oil production process with high waste burden for the environment, it becomes evident that their exploitation could increase their added value. Therefore, in this study the potential antioxidant action of four olive flower extracts was investigated. All the extracts exerted potent antioxidant activity as indicated using the DPPH center dot and ABTS(center dot+) assays, as well as antigenotoxic and antimutagenic properties, identified by the results of the plasmid relaxation assay and the Ames test, respectively. Furthermore, the extracts also improved redox status of four cell lines (i.e., EA.hy926, C2C12, HeLa, and HepG2) enhancing reduced glutathione and reducing reactive oxygen species levels using flow cytometry. Taking into account that during olive tree cultivation a considerable amount of olive flowers is generated, the waste burden is high and the management is difficult. Given the optimistic findings of the present study, we believe that the flower-derived extracts may have high added value since they could be used as antioxidants or as foodstuff, food additives and functional food constituents.

JIF:3.04

Follistatin-like protein 1 knockdown elicits human gastric cancer cell apoptosis via a STAT6-dependent pathway

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Gastric cancer is an aggressive disease and a common cause of cancer-associated mortality worldwide. Recent studies have indicated that follistatin-like protein 1 (FSTL-1) is expressed and serves essential roles in tumorigenesis; however, the specific functional mechanism of FSTL-1 in gastric cancer progression remains ambiguous. CellTiter-Glo Luminescent Cell Viability and lactate dehydrogenase assays were used to measure cell survival and cell cytotoxicity, respectively. Cell apoptosis was ascertained using the Cell Death Detection ELISA assay and caspase-3/9 activity kits. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the expression levels of FSTL-1. The present study confirmed that FSTL-1 was highly expressed in gastric cancer cells compared with in control cells. Subsequently, FSTL-1 inhibition by small interfering RNA significantly reduced cancer cell survival and induced cytotoxic effects. In addition, knockdown of FSTL-1 in gastric cancer cells promoted apoptosis by increasing caspase-3 and caspase-9 expression. A decrease in signal transducer and activator of transcription 6 (STAT6) phosphorylation was observed in FSTL-1 knockdown cells, and the results confirmed that STAT6 phosphorylation was essential for FSTL-1 knockdown-induced cell apoptosis of cancer cells. Taken together, these results demonstrated that FSTL-1 knockdown may promote cell apoptosis via the STAT6 signaling pathway; therefore, FSTL1 may be considered a novel diagnostic and therapeutic target for gastric cancer.

JIF:3.04

Suppressive effects of the sodium-glucose cotransporter 2 inhibitor tofogliflozin on colorectal tumorigenesis in diabetic and obese mice

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Sodium-glucose cotransporter 2 inhibitors were developed for the treatment of diabetes mellitus. Although recent studies have indicated that sodium-glucose cotransporter 2 inhibitors have suppressive effects on several types of cancer, their effects against colorectal cancer remain unknown. The purpose of the present study was to investigate the effects of tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, on the development of colorectal cancer in diabetic and obese mice. The direct effects of tofogliflozin on the proliferation of colorectal cancer cells were also evaluated. C57BL/KsJ-db/db mice were injected with azoxymethane to induce colorectal pre-malignancy and they received drinking water with or without tofogliflozin. At the end of the study, administration of tofogliflozin was revealed to significantly suppress the development of colorectal neoplastic lesions and beta-catenin accumulated crypts. In the tofogliflozin-treated mice, the levels of blood glucose and serum TNF-alpha, as well as mRNA expression of the pro-inflammatory markers in the white adipose tissue, were reduced. Furthermore, macrophage infiltrations in the white adipose tissues were also reduced significantly. The proliferation of the sodium-glucose cotransporter 2-expressing human colorectal cancer cells was not altered by tofogliflozin. These results indicated that tofogliflozin ameliorated chronic inflammation and hyperglycemic condition leading to prevention of colorectal tumorigenesis in a diabetes- and obesity-related colorectal cancer model.

JIF:3.04

Palmitoylome profiling indicates that androgens regulate the palmitoylation of alpha-tubulin in prostate cancer-derived LNCaP cells and supernatants

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Prostate cancer is closely associated with constitutive transactivation of the androgen receptor (AR) signaling pathway. After treatment with androgen-deprivation therapy (ADT), the majority of patients develop castration-resistant prostate cancer within months or years. In order to investigate potential novel therapeutic targets in addition to ADT, the present study examined the regulatory mechanisms of the AR signaling pathway. In the present study, LNCaP cells were metabolically-labeled with Alk-C16, a palmitate probe. In addition, cells were treated with R1881, an androgen, or DMSO. Subsequently, click-chemistry-based palmitoylome profiling was performed in LNCaP cells and palmitoylated proteins were compared between cells treated with androgen and untreated cells. Androgen treatment was revealed to significantly increase the palmitoylation level of alpha-tubulin. In addition, the palmitoylation level of Ras-related protein Rab-7a (Rab7a) was enhanced by androgen treatment. Palmitoylation of alpha-tubulin and Rab7a were essential for cell proliferation. Notably, in the supernatant of LNCaP cells, the palmitoylation level of alpha-tubulin was also increased following androgen treatment. Palmitoylation of alpha-tubulin may provide a new potential target for the treatment of prostate cancer. In addition, the high level of alpha-tubulin palmitoylation in the supernatant may represent a biomarker for early-stage prostate cancer.

JIF:3.04

RSK4 inhibits breast cancer cell proliferation and invasion in vitro, and is correlated with estrogen receptor upregulation in breast cancer

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Estrogen (E2) receptor (ER) upregulation has been associated with tumor progression and is the most commonly used clinical biomarker in breast cancer. X-linked ribosomal S6 kinase 4 (RSK4) is downregulated in breast cancer and may act as a tumor suppressor gene. In order to understand the association between the ER and RSK4, the present study studied the effects of RSK4 on ER-positive (ER+) breast cancer cell function, and the effects of E2 on RSK4 function and RSK4 methylation. Furthermore, the disease-free survival of patients with breast cancer with RSK4 hypermethylation/hypomethylation was investigated to establish the link between RSK4 methylation on patient prognosis. The expression levels of RSK4 were increased and RSK4 promoter methylation was decreased in ER+ breast cancer tissues and cell lines compared with ER-negative breast cancer tissues and cell lines, respectively. ER expression was negatively correlated with RSK4 expression and positively associated with RSK4 methylation. In vitro overexpression of RSK4 decreased the proliferation, clone formation, migration and angiogenesis and increased apoptosis of breast cancer cells. Patients with RSK4 hypomethylation exhibited a longer disease-free survival compared with patients with RSK4 hypermethylation. E2 stimulation of breast cancer cells increased ER expression and RSK4 methylation, which was associated with decreased RSK4 expression. Furthermore, ER upregulation was proposed to be related to the decreased expression of RSK4 in ER+ breast cancer. E2 signaling may therefore act upstream of RSK4 to promote cancer progression. The results obtained in the current study suggested that RSK4 inhibited breast cancer cell invasiveness and that RSK4 promoter hypomethylation may serve as a novel prognostic marker for patients with breast cancer.

JIF:3.04

Targeting YAP suppresses ovarian cancer progression through regulation of the PI3K/Akt/mTOR pathway

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Ovarian cancer (OC) is highly metastatic due to frequent peritoneal dissemination, and its treatment poses a major challenge in clinical practice. Yes-associated protein (YAP) is known to be associated with the development of multiple tumors. However, whether targeting YAP can restrain OC progression and the underlying mechanisms have yet to be fully elucidated. In the present study, YAP was found to be highly expressed in OC, and its expression was correlated with the prognosis of OC patients. Moreover, silencing of YAP markedly inhibited the malignant behavior of OC cells, possibly through regulation of the PI3K/Akt/mTOR pathway. Notably, peptide 17, a YAP inhibitor, exerted a significant attenuating effect on OC progression by diminishing the activation of the PI3K/Akt/mTOR pathway in vitro as well as in vivo. Taken together, these findings demonstrated that targeting YAP attenuated OC progression and suggested the potential application of peptide 17 in OC therapy, thus providing new insights into improving the treatment of OC.

JIF:3.04

Downregulation of miR-143 modulates KRAS expression in colorectal carcinoma cells

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

MicroRNAs (miRs) are a class of non-coding small RNAs that have been demonstrated to be involved in the pathogenesis of human cancer. There is even evidence that microRNAs can act as oncogenes or tumor suppressors. Although microRNA expression profiles have been characterized in colorectal carcinoma, their precise physiological functions are largely unknown. It has become clear that the activated KRAS Proto-Oncogene, GTPase (KRAS) oncogene plays an important role in colorectal carcinogenesis. In the present study, it was found that the level of mature miR-143 was lower in colorectal carcinoma tissues compared with that observed in normal adjacent tissues. A lack of miR-143 was detected in human colorectal carcinoma cell lines, SW480, LoVo and HT-29, compared to the high expression observed in normal colon epithelial cell line NCM460. pcDNA3.1-pri-miR-143 and its mutant were successfully constructed and transfected into colorectal carcinoma cells. Increased accumulation of mature miR-143 was observed in the pcDNA3.1-pri-miR-143-transfected cells. In SW480 cells, transfection of pcDNA3.1-pri-miR-143 resulted in a 35 and 47% reduction in cell growth after incubation for 4 and 5 days, respectively, compared with transfection of the pcDNA3.1-pri-miR-143 mutant; while in LoVo cells, transfection of pcDNA3.1-pri-miR-143 resulted in a 33 and 46% reduction in cell growth respectively. In contrast, transfection of pcDNA3.1-pri-miR-143 had no significantly effects on HT-29 cell growth. We also found that transfection of pcDNA3.1-pri-miR-143 had no effect on levels of KRAS mRNA, but resulted in a 58% decrease in the KRAS protein level in the transfected SW480 cells, while an approximate 54 and 43% KRAS protein reduction in LoVo and HT-29 cells, respectively, compared with the pcDNA3.1-pri-miR-143 mutant. Two fragments containing the putative complementary site were cloned into the pGL3 vector, constructing the luciferase reporter pGL3-KRAS-CS1 and pGL3-KRAS-CS2. Cotransfection of pcDNA3.1-pri-miR-143 with pGL3-KRAS-CS1 and pGL3-KRAS-CS2 respectively resulted in 4.6- and 3.3-fold inhibition of luciferase activity in the SW480 cells, while a 4.0- and 3.2-fold inhibition of luciferase activity in the LoVo cells, 3.7- and 3.1-fold inhibition in the HT-29 cells. Differences in pGL3-KRAS-CS1 and pGL3-KRAS-CS2 activity were not significant. Our results revealed that increased accumulation of miR-143 is likely to modulate levels of KRAS protein expression at the post-transcriptional level by interacting specifically with the complementary site, and consequently inhibiting proliferation of the transfected cells.

JIF:3.04

High levels of Notch intracellular cleaved domain are associated with stemness and reduced bevacizumab efficacy in patients with advanced colon cancer

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

delta-like ligand 4 (DLL4)-Notch signaling is associated with tumor resistance to anti-vascular endothelial growth factor (VEGF) therapy. Furthermore, Notch signaling is critical for the maintenance of colon cancer stem cells (CSCs), which are relevant in drug resistance and tumor angiogenesis. CD44 is a transmembrane glycoprotein and is considered a putative marker of CSCs. To assess the association of Notch intracellular cleaved domain (NICD), DLL4 and CD44 expression with the efficacy of anti-angiogenic drugs, a series of samples derived from patients with advanced colon cancer enrolled in prospective clinical trials were analyzed. Histological samples from 51 primary tumors that originated from patients treated with bevacizumab-based first-line chemotherapy were analyzed by immunohistochemistry for NICD, DLL4 and CD44 expression, and CD31 for microvessel count. The expression levels of genes relevant for angiogenesis [angiopoietin (ANGPT)1, ANGPT2, fibroblast growth factor (FGF)1, FGF2, epidermal growth factor, placental growth factor, VEGFA and DLL4] were detected by reverse transcription-quantitative PCR using RNA extracted from the frozen tissues of four tumors with low and four tumors with high NICD expression. Strong NICD levels were observed in 12/51 (24%) of the patients, whereas 16/51 (31%) of the colon cancer subjects exhibited high CD44 expression. Strong CD44 staining was associated with high NICD levels compared with the CD44 expression levels noted in samples with low NICD levels (67 vs. 20%, P=0.005). No association was observed with regards to the expression levels of NICD, CD44 and the other aforementioned biomarkers. High expression levels of NICD and CD44 predicted reduced progression-free survival (P<0.001) and overall survival (P=0.002). No significant differences in the expression of angiogenesis-related genes were detected between low and high NICD-expressing tumors. In conclusion, NICD and CD44 tissue levels exhibited an association and may be related to a reduced survival rate in patients with advanced colon cancer treated with bevacizumab.

JIF:3.04

Microarray profile of circular RNAs identifies hsa_circRNA_102459 and hsa_circRNA_043621 as important regulators in oral squamous cell carcinoma

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Circular RNAs (circRNAs) have emerged as important regulators of carcinogenesis. However, the role of circRNAs in oral squamous cell carcinoma (OSCC) remains limited. Here, total RNAs were extracted from three pairs of OSCC and adjacent normal tissues and subjected to circRNA microarrays to detect the differentially expressed circRNAs. Gene Ontology (GO) and functional category analyses were used to identify circRNAs associated with tumor cell proliferation pathways. Then, gain-of-function assays or loss-of-function assays were conducted to investigate the functions of the most upregulated and downregulated circRNAs on TSCC1 cell proliferation, cell cycle and apoptosis using CCK-8 and EdU assays, flow cytometry and Hoechst 33258 staining, respectively. The results revealed that hsa_circRNA_102459 was significantly downregulated and hsa_circRNA_043621 was significantly upregulated in OSCC tissues. Clinical stage, tumor differentiation, lymph node metastasis presented significant difference in regards to the expression of circRNA_043621 and circRNA_102459. The in vitro experiments further demonstrated that upregulation of circRNA_102459 or downregulation of circRNA_043621 significantly suppressed TSCC1 cell proliferation, induced cell cycle G0/G1 phase arrest and promoted apoptosis. Furthermore, the MAPK and PI3K/Akt pathways were suppressed, while Bcl-2 family members were activated by circRNA_102459 overexpression and circRNA_043621 knockdown. Taken together, our study indicates that differentially expressed circRNAs are closely related to the carcinogenesis of OSCC. Among these, circRNA_102459 and circRNA_043621 may function as a tumor-suppressor and promoter, respectively, of OSCC carcinogenesis, and thus may be valuable diagnostic biomarkers of OSCC.

JIF:3.04

Upregulation of circular RNA circ-FAM53B predicts adverse prognosis and accelerates the progression of ovarian cancer via the miR-646/VAMP2 and miR-647/MDM2 signaling pathways

期刊: ONCOLOGY REPORTS, 2019; 42 (6)

Ovarian cancer (OC) is a common cancer of the human genital system. Circular RNAs (circRNAs) play an important role in carcinogenesis and progression of various cancers. The present study aimed to clarify the expression profile and functions of circ-FAM53B in the progression of OC and reveal its underlying mechanisms. Relative levels of circ-FAM53B in OC specimens and cell lines were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The clinical significance of circ-FAM53B in OC patients was analyzed through Fisher's exact test, Kaplan-Meier curves, and Cox regression analysis. Subsequently, the regulatory effects of circ-FAM53B on the proliferative, apoptotic, migratory, and invasive potential of OC cells were determined by loss/gain-of-function experiments. Mechanistically, bioinformatics analysis and luciferase reporter gene assay were used to reveal the potential molecular mechanisms of circ-FAM53B in OC. circ-FAM53B was overexpressed in OC specimens and cells and correlated with clinical severity and poor prognosis of OC patients. The overexpression of circ-FAM53B accelerated the proliferation, migration, and invasion of HO8910 cells; however, it decreased the number of apoptotic cells. Silencing of circ-FAM53B induced the opposite effect. Through dual-luciferase reporter gene assay and functional experiments, the potential functions of circ-FAM53B/miRNA-646/vesicle-associated membrane protein 2 (VAMP2) and circ-FAM53B/miRNA-647/mouse double minute 2 (MDM2) in mediating the progression of OC were identified. Collectively, the present results indicated that circ-FAM53B could be a competing endogenous RNA (ceRNA) to competitively sponge miR-646 and miR-647 to upregulate VAMP2 and MDM2 expression at the post-transcriptional level, thus mediating the cellular behaviors of OC cells.

JIF:3.04

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