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Purpose Macrophages are a major component of the tumour microenvironment and play an important role in chemoresistance of cancer. However, how exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of doxorubicin resistance in gastric cancer (GC) are not clearly defined. The aim of this study was to investigate whether macrophage-derived exosomes mediate doxorubicin resistance in GC. Methods Exosomes isolated from macrophage culture medium were characterized and co-cultured with GC cells and the miR-223 level was detected using real-time quantitative PCR (RT-qPCR). The internalization of exosomes and transfer of miR-223 were observed via immunofluorescence. Macrophages were transfected with an miR-223 inhibitor or negative control. Cell Counting Kit-8 and flow cytometry were employed to explore the effect of macrophage-derived exosomes on the doxorubicin resistance of GC cells. Western blot and RT-qPCR assay were also performed to explore the regulation of GC chemotherapy resistance by exosomal miR-223. Results Here, the macrophages and macrophage-derived exosomes promoted doxorubicin resistance in GC cells. MiR-223 was enriched in macrophage-derived exosomes and they could be transferred to co-cultivated GC cells. The miR-223 knockdown in macrophages could reduce the effects of exosomes on GC cells. Functional studies revealed that exosomal miR-223 derived from macrophages promoted doxorubicin resistance in GC cells by inhibiting F-box and WD repeat domain-containing 7 (FBXW7). Clinically, the expression of miR-223 significantly increased in GC tissues and high expression of plasma exosomal miR-223 was highly linked with doxorubicin resistance in GC patients. Conclusion The exosomal transfer of macrophage-derived miR-223 conferred doxorubicin resistance in GC and targeting exosome communication may be a promising new therapeutic strategy for GC patients.

Purpose Several lines of evidence support the fact that the presence of oxidative stress plays an important role in the pathophysiological mechanisms of schizophrenia (SCZ). The glutathione peroxidases (GPXs) and glutathione S-transferases (GSTs) are the major antioxidant enzymes. Polymorphic variants of GPX and GST can affect the antioxidant activities of their encoded enzymes. This study explored the possible associations of the GSTA1 and GPX3 gene polymorphisms and schizophrenia in Chinese Han population. Methods DNA from 648 healthy controls and 617 schizophrenic patients was genotyped for single-nucleotide polymorphisms (SNPs) rs3957357 in GSTA1 and rs736775 in GPX3 using a PCR-LDR genotyping assay. The χ2 test compared differences in genetic distributions between the two groups in a case-control study. The generalized multifactor dimensionality reduction (GMDR) was used to explore the interaction between the GSTA1 gene and the GPX3 gene on the risk of SCZ. Results Significant differences in allelic and genotypic frequencies of GSTA1 rs3957357 were present between SCZ and control groups (GSTA1 rs3957357 χ2=6.172, P=0.046 by genotype, χ2=5.847, P=0.016, odds ratio=1.329, 95% confidence interval=1.055-1.674 by allele). No significant differences in allelic or genotypic frequencies of GPX3 rs736775 were detected between cases and controls (GPX3 rs736775: χ2=2.058, P=0.357 by genotype, χ2=1.853, P=0.173, odds ratio=1.131, 95% confidence interval=0.953-1.342 by allele). Moreover, the GMDR model showed that the interaction between GSTA1 rs3957357 and GPX3 rs736775 was associated significantly with SCZ risk, P=0.0107. Conclusion Our results suggest that GSTA1 rs3957357 SNP has an effect on the risk of SCZ and the interaction between GSTA1 rs3957357and GPX3 rs736775 may affect the development of SCZ in Chinese Han population. However, these results should be validated by replication in different populations with large sample sizes.

MicroRNAs (miRNAs) are a class of gene expression regulators that participate in the occurrence and development of hepatocellular carcinoma (HCC), although the underlying mechanism by which they function in HCC has not been fully elucidated. Here, small RNA deep sequencing was used to identify aberrantly expressed miRNAs in HCC tissues, and a novel miRNA named miR-HCC2 was identified. RT-qPCR analysis demonstrated that miR-HCC2 displayed higher expression in HCC tissues than in adjacent non-tumor tissues. We documented that miR-HCC2 facilitated the growth, migration and invasion of HCC cells by accelerating cell cycle progression, incressing the expression of epithelial-to-mesenchymal transition (EMT)-associated marker vimentin but decreasing the expression of E-cadherin. MiR-HCC2 directly targeted the 3' UTR of BAMBI and ELMO1 and up-regulated their expression. Both BAMBI and ELMO1 had the same patterns of expression with miR-HCC2 in HCC tissues. Additionally, blocking BAMBI or ELMO1 counteracted the phenotypic alterations elicited by miR-HCC2. Collectively, our investigation identified miR-HCC2 as a new positive modulator of HCC aggressiveness that may serve as a potential biomarker for the development of diagnostic and therapeutic approaches for HCC.

Hepatocellular carcinoma (HCC) is one of the most aggressive malignant diseases and requires more effective prevention and treatment strategies. Mutations or overexpression of endoplasmic reticulum (ER) proteins have been frequently identified in a solid tumor, suggesting that ER proteins play an important role in tumor development. SEC61G, a component of Sec61 complex located in the membrane of the human ER, has been revealed a potential relevance in glioblastoma multiforme. Analyses from TCGA database showed that SEC61G was overexpressed in HCC. Additionally, the expression of SEC61G mRNA was associated with the survival time of HCC patients. We verified that the higher expression of SEC61G in HCC tissues than paracancerous tissues. Moreover, knockdown of SEC61G inhibited cell proliferation and induced cell apoptosis in vitro. Besides, SEC61G was required for cell migration and invasion, conferring a potential role for SEC61G in tumor transfer. Taken together, our results revealed the role of SEC61G in HCC cells. Further detailed understanding of the signaling networks underlying SEC61G involvement in HCC cells would make SEC61G as a viable therapeutic target for pharmaceutical intervention of HCC.

Multiple pieces of evidence illustrate that impaired trophoblast function results in preeclampsia (PE), and migration/invasion of human trophoblast cells is stringently regulated by extracellular matrix (ECM) components. Many studies have indicated abnormal expressions of placental ECM components are associated with preeclampsia. However, the change and influence of lumican, a vital member of extracellular matrix (ECM) molecules, on trophoblast cells during preeclampsia remain unclear. This study examines the possibility that the roles of lumican in trophoblast cells contribute to PE. To address this issue, the expression of lumican in human placental tissues was observed using immunohistochemistry, fluorescence quantitative PCR, and Western blot technology. After the HTR-8/SVneo cell line was transfected with pcDNA3.1-human lumican, pGPU6-human lumican shRNA, and their negative controls, the impact of lumican on the HTR-8/SVneo cell line was investigated. Lumican was expressed in human placental tissues. Compared with the control group, its expression was significantly lower in PE placentas. Lumican downregulation inhibited cell proliferation significantly and reduced Bcl-2 expression, but increased P53 expression. These results indicate that the downregulation of placental lumican may drive PE development via promoting the downregulation of Bcl-2 expression and upregulation of P53.

Serotonin (5-HT) is a monoamine and it could regulate cell growth by its receptors working on signaling pathways. 5-HTP is the precursor of 5-HT that help 5-HT synthesis. B cell leukemia/lymphoma 3 (Bcl-3) involved in cell death and proliferation through mitogen activated protein kinase (MAPK) pathway. However, there is little information about the effects of MAPK/Bcl-3 on apoptosis of goat mammary gland epithelial cells (GMECs). The aim of this study is to explore the interaction among 5-HTP, MAPK and Bcl-3 in GMEC apoptosis. In this study, 5-HTP treatment decreased cell apoptosis and promoted phosphorylation of ERK1/2 in GMEC. We also found that the activation and inhibition of ERK1/2 could affect GMEC apoptosis. The Annexin V-FITC/PI staining and western blotting results suggested that 5-HTP decreased GMEC apoptosis through ERK1/2 signaling pathway. And the results of RT-qPCR and western blotting demonstrated that both 5-HTP and ERK1/2 positively regulated Bcl-3 expression. Sum up all the results, we could draw the conclusion that 5-HTP decreased GMEC apoptosis through MAPK/ERK/Bcl-3 pathway.

Increasing lines of evidence show that oxidative stress plays a role in the pathophysiological mechanisms of schizophrenia (SCZ). Polymorphic variants of oxidative stress-related candidate genes GPX1 and GST1 can affect the antioxidant activities of their encoded enzymes. Therefore, this study aimed to explore the association between the single nucleotide polymorphisms (SNPs) of GPX1 and GSTP1 and susceptibility to schizophrenia in the Chinese Han population. DNA from 323 healthy controls and 210 schizophrenic patients was genotyped for SNPs rs1050450 in GPX1 and rs1695 in GSTP1 using a predesigned TaqMan SNP genotyping assay. Differences in genetic distributions between cases and controls were compared using the χ-test. No significant differences in allelic or genotypic frequencies of GPX1 rs1050450 or GSTP1 rs1695 were detected between cases and controls (GPX1 rs1050450: χ=0.370, P=0.831 by genotype, χ=0.377, P=0.539, odds ratio=1.145, 95% confidence interval=0.743-1.766 by allele; GSTP1 rs1695: χ=1.537, P=0.464 by genotype, χ=1.623, P=0.203, odds ratio=0.813, 95% confidence interval=0.592-1.118 by allele). Our results suggest that GPX1 rs1050450 and GSTP1 rs1695 SNPs are unlikely to play a major role in the pathogenesis of schizophrenia in the Chinese Han population. However, these results should be validated by replication in larger and independent samples.

Ligustrum vicaryi L. is a hybrid of Ligustrum ovalifolium Hassk. var. aureo-marginatum and Ligustrum vulgale L., belonging to the Oleaceae family. It is often used as an ornamental shrub due to its golden leaves. However, its medical value is yet to be discovered. Recently, plant polysaccharides have attracted comprehensive attention owing to their biological properties, including immunomodulatory and antioxidant activities. This study aimed to extract, purify, and characterize the polysaccharide from the Ligustrum vicaryi L. fruit and investigate its immunomodulatory and antioxidant activities. The Ligustrum vicaryi L. fruit polysaccharide (LVFP) was obtained by ultrasonic extraction, ethanol precipitation, macroporous resin separation, and dialysis bag purification. The physicochemical properties of the LVFP were elucidated using Fourier-transform infrared spectrometry, high-performance ion chromatography, and high-performance gel filtration chromatography. The results indicated that the LVFP consisted of rhamnose, arabinose, galactose, and glucose in a ratio of 1.79 : 7.55 : 4.58 : 1.54, and its molecular weight was 88,949 Da. The immunomodulatory and antioxidant activities of the LVFP were investigated using a cyclophosphamide- (Cy-) induced immunosuppressed mouse model. The results demonstrated that the LVFP significantly increased spleen and thymus indexes, enhanced the phagocytic function of neutrophils, activated B and T lymphocytes, and upregulated serum levels of IL-10 and TNF-α. Moreover, we observed that the LVFP relieved Cy-induced liver damage by increasing superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) levels. These results suggested that the LVFP has the immunomodulatory and antioxidant activities, therefore laying a foundation for the application of the LVFP in the pharmaceutical and functional food industries.

Objective Each pulmonary segment is an anatomical and functional unit. However, it is fundamentally difficult to precisely distinguish every pulmonary segment using the conventional pulmonary intersegmental planes from computed tomography images. Building arteriopulmonary segments is likely to be an effective way to identify pulmonary segments. Methods The thoracic computed tomography images of 40 patients were collected. The anatomic structures of interest were extracted in the transverse, sagittal, and coronal planes using the semi-automated segmentation tools provided by Amira software. The intrapulmonary vessels were subsequently segmented and reconstructed. The distributions of the pulmonary arteries, veins, and bronchi were observed. In patients with pulmonary masses, the mass was also reconstructed. Results The three-dimensional reconstructed images showed the branches of the pulmonary artery ramified up to their eighth order covering the entire lung as well as evident intersegmental gaps without pulmonary arteries. The segmental artery was closely accompanied by the segmental bronchi in 486 pulmonary segments (90% of total number of segments). The size and spatial location of the pulmonary mass within a pulmonary segment were also clearly visible. Conclusions Demarcation of arteriopulmonary segments can be used to precisely distinguish every pulmonary segment and provide its detailed anatomical structure before pulmonary segmentectomy.

Dysregulation of microRNAs (miRNAs) can contribute to tumorigenesis in cancers. In this study, we found that miR-429 was downregulated in cervical cancer (CC) tissues and suppressed cell viability and proliferation while promoting apoptosis in CC cells. IKKβ was a novel target gene of miR-429 and ectopic expression of IKKβ abrogated the phenotypes induced by miR-429. When IKKβ was downregulated by miR-429, nuclear factor κB (NF-κB) pathway activation, interleukin-6 (IL-6), and interferon-β (IFN-β) production were decreased in CC cells. These findings indicate that miR-429 is involved in regulation of the NF-κB pathway by targeting IKKβ and functions as a tumor suppressor in cervical carcinogenesis.

Background/Aims: Increasing evidence shows that oxidative stress plays an important part in the pathophysiological mechanisms of preeclampsia (PE). Polymorphic variants of oxidative stress-related candidate genes GST1 and GPX1 can affect the antioxidant activities of their encoded enzymes. Therefore, this study aimed to explore the associational analysis between GSTP1 and GPX1 single nucleotide polymorphisms (SNPs) and susceptibility to PE in Chinese Han women. Methods: DNA from 1130 PE patients and 1226 healthy individuals was genotyped for SNPs rs1695 in GSTP1 and rs1050450 in GPX1 using a predesigned TaqMan SNP genotyping assay. The χ2 test compared differences in genetic distributions between the two groups in a case-control study. Results: No significant differences in allelic or genotypic frequencies of GSTP1 rs1695 or GPX1 rs1050450 were detected between cases and controls (GSTP1 rs1695: χ2=1.122, p=0.571 by genotype, χ2=0.138, p=0.710, odds ratio=1.027, 95% confidence interval 0.892-1.183 by allele; GPX1 rs1050450: χ2=0.036, p=0.982 by genotype, χ2=0.002, p=0.960, odds ratio=1.005, 95% confidence interval 0.822-1.229 by allele). Moreover, no significant differences in genetic distribution were found between early/late-onset PE or mild/severe PE and control subgroups. Conclusion: Our results suggest that GSTP1 rs1695 and GPX1 rs1050450 SNPs have no effects on the risk of PE in the Chinese Han population. However, these results should be confirmed by replication in different populations.

Multiple primary cancer (MPC) is relatively rare. With the development of diagnostic and anti-cancer therapeutic techniques, the incidence of MPC is rising annually. However, the incidence of triple or quadruple cancers in a single patient remains low. In this report, the case of a 58-year-old male with triple malignant cancer is outlined. Synchronous sigmoid colon cancer and thyroid cancer were diagnosed in May 2015; on subsequent re-examination, metastasis to the liver and a malignant kidney tumor were also identified. The diagnosis was established via computed tomography (CT), Positron emission tomography-CT (PET-CT) and other laboratory examination results, including analysis of tumor markers and liver function, and was confirmed by pathological diagnosis. The patient underwent radical surgery and standardized chemotherapy. Through literature review, the definition, characteristics, classification, incidence, possible causes of and treatment strategies for MPC were more clearly understood. In addition, immunohistochemical staining of integrin αvβ6 was performed on patient tissue specimens, where integrin αvβ6 expression was confirmed in cancer of the colon, thyroid and liver, as a result of colonic metastasis. Therefore, the involvement of integrin αvβ6 in the malignant progression of MPC was hypothesized, which may aid the investigation of MPC etiology in the future.

Tumor microenvironment (TME) is the cellular environment in which tumor exists, and it contributes to tumor formation and progression. The TME is composed of tumor cells, stromal cells, cytokines, and chemotactic factors of which fibroblasts are the main cellular components. In our present study, we found that colorectal cancer (CRC) cells expressing integrin αvβ6 clearly could induce morphological changes in inactive fibroblasts and increased the expression of activated fibroblast markers such as α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Those activated fibroblasts in the TME are called cancer-associated fibroblasts (CAFs). In order to investigate the mechanism by which CRC cells expressing integrin αvβ6 activated CAFs, a series of assays have been carried out in the follow-up. We found that CRC cells could secrete inactive transforming growth factor β (TGF-β); however, integrin αvβ6 activated TGF-β, which subsequently activated fibroblasts. This process was disrupted by knockdown of integrin αvβ6. In contrast, activated fibroblasts could promote CRC cell invasion. In particular, the strengthening effect on expression of integrin αvβ6 in colon cancer cells was obvious. Additionally, we found that CAFs could secrete stromal cell-derived factor-1 (SDF-1) and promote CRC cell metastasis in distant organs via the SDF-1/C–X–C chemokine receptor type 4 (CXCR4) axis. Taken together, we assumed that CRC cells and CAFs activated one another and worked together to promote cancer progression, with integrin αvβ6 playing a role in the bi-directional regulation of these cells. Hence, integrin αvβ6 may serve as a therapeutic target for the future CRC treatment.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers. It has been demonstrated that various cellular microRNAs (miRNAs) play an important role in HCC development. Here, we analyzed the miRNA profile in HCC tissues by Solexa sequencing, and we identified a novel microRNA, miR-HCC1, which is upregulated in HCC tissues. Further experiments showed that miR-HCC1 promoted HCC cell proliferation in vivo and in vitro, and migration and invasion resulting from the epithelial-mesenchymal transition (EMT) process. Nuclear factor I/X (NFIX), which inhibited cell proliferation, migration and invasion in HCC cells, was identified as a direct and functional target of miR-HCC1. Furthermore, lymphoid enhancer binding factor 1 (LEF1), a transcription factor, was shown to bind the promoter of miR-HCC1 and activate its expression. Collectively, these results indicate that LEF1-upregulated miR-HCC1 functions as an oncogene through the negative regulation of NFIX expression, which links the LEF1/miR-HCC1/NFIX axis to contribute to cell proliferation, migration and invasion of HCC cells and could provide novel insights into miRNA function and hepatocarcinogenesis and potential biomarkers for HCC.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly cancers and is expected to become the second leading cause of cancer death by 2030. Despite extensive efforts to improve surgical treatment, limited progress has been made. Increasing evidence indicates that integrin β6 plays a crucial role in carcinoma invasion and metastasis. However, the expression and role of β6 in PDAC remain largely unknown. In the present study, we investigated the expression of β6 in PDAC and its potential value as a prognostic factor and therapeutic target. β6 upregulation was identified as an independent unfavorable prognostic indicator. Integrin β6 markedly promoted the proliferation and invasion of pancreatic carcinoma cells and induced ETS1 phosphorylation in an ERK-dependent manner, leading to the upregulation of matrix metalloprotease-9, which is essential for β6-mediated invasiveness of pancreatic carcinoma cells. Accordingly, small interfering RNA-mediated silencing of integrin β6 markedly suppressed xenograft tumor growth in vivo. Taken together, our results suggest that integrin β6 plays important roles in the progression of pancreatic carcinoma and contributes to reduced survival times, and may serve as a novel therapeutic target for the treatment of PDAC.

Background The increase in the prevalence of end-stage renal disease in developed countries and the shortage of deceased donors have made it necessary to increase the graft pool by means of several strategies, such as living donation, non–heart-beating organ donors, and expanded-criteria donors. This study aimed to assess the short-term outcomes of donor kidneys with small (≤3.5 cm) renal cell carcinoma (sRCC) and to evaluate the possibility of using marginal kidneys in renal transplantation. Methods Patients undergoing nephrectomy for sRCC who agreed to donate their kidneys were enrolled in the study. Seven dialysis patients aged 27-54 years agreed to undergo transplantation with sRCC kidneys. All of the transplantations were performed in Shandong Province Qianfoshan Hospital from May 2012 to March 2017. The function of transplanted kidneys was evaluated after surgery by testing and comparing parameters such as creatinine clearance rate, delayed graft function, and tumor recurrence. Results The graft function of the transplanted kidneys was recovered to normal in all of the 7 patients who received sRCC kidneys. The latest serum creatinine levels before publication ranged from 59 to 102 μmol/L in the 7 recipients (normal range of serum creatinine: men, 54-106 μmol/L; women, 44-97 μmol/L). No tumor recurrence was noted 31-58 months after surgery in the recipients. Conclusions According to short-term follow up (3-5 years), kidney transplantation in selected patients can be considered for kidneys having small incidental tumors. The use of marginal organs, such as those with sRCC, can increase the donor pool for kidney transplantation.

MicroRNA (miRNA) dysregulation has been associated with carcinogenesis in many cancers, including human colorectal cancer (hCRC). However, the effect and mechanism of miR-377-3p on CRC remains elusive. Herein, we first found that miR-377-3p was upregulated in CRC tissues and promoted tumorigenic activity by accelerating the G1 -S phase transition, promoting cell proliferation and epithelial-mesenchymal transition (EMT) while repressing apoptosis in CRC cells. Glycogen synthase kinase-3β (GSK-3β) was a direct target of miR-377-3p, and upregulated by miR-377-3p. Knockdown of GSK-3β partly rescued miR-377-3p-mediated malignancy characteristics. Most importantly, we showed that miR-377-3p promoted carcinogenesis by activating NF-κB pathway. Taken together, our results first reported that miR-377-3p functions as an oncogene and promotes carcinogenesis via upregulating GSK-3β expression and activating NF-κB pathway in hCRC cells.

Norcantharidin (NCTD) is an efficacious anti-cancer drug that has been used in China for many years, but its underlying mechanism of action is still not fully understood. In the present study, we found that NCTD could induce morphological changes in colon cancer cells, causing a transition from a spindle-shaped morphology to a typical round or oval shape, which was indicative of a mesenchymal-epithelial transition (MET) process. Next, we investigated the mechanism by which NCTD induced the MET process. Using a transwell assay, we found that NCTD could suppress the migratory and invasive ability of colon cancer cells in a dose-dependent manner. Moreover, NCTD suppressed the expression of integrin αvβ6, MMP-3 and MMP-9 as well as the polymerization of F-actin, further supporting its suppressive effect on migratory and invasive ability. Furthermore, the expression of αvβ6, N-cadherin, vimentin and phosphorylated ERK was decreased, while the expression of E-cadherin was up-regulated. We verified that phosphorylated Ets1 was down-regulated substantially after treatment with NCTD. Taken together, our data demonstrated that NCTD could inhibit the EMT process of colon cancer cells by inhibiting the αvβ6-ERK-Ets1 signaling pathway. This study revealed part of the mechanism through which NCTD could reverse the EMT process in colon cancer.