Correlation between second and first primary cancer: systematic review and meta-analysis of 9 million cancer patients.

BACKGROUND: Many survivors of a first primary cancer (FPCs) are at risk of developing a second primary cancer (SPC), with effects on patient prognosis. Primary cancers have different frequencies of specific SPC development and the development of SPCs may be closely related to the FPC. The aim of this study was to explore possible correlations between SPCs and FPCs. METHODS: Relevant literature on SPCs was retrospectively searched and screened from four databases, namely, PubMed, EMBASE, Web of Science, and PMC. Data on the number of patients with SPC in 28 different organ sites were also collected from The Surveillance, Epidemiology, and End Results (SEER) 8 Registry and NHANES database. RESULTS: A total of 9 617 643 patients with an FPC and 677 430 patients with an SPC were included in the meta-analysis. Patients with a first primary gynaecological cancer and thyroid cancer frequently developed a second primary breast cancer and colorectal cancer. Moreover, those with a first primary head and neck cancer, anal cancer and oesophageal cancer developed a second primary lung cancer more frequently. A second primary lung cancer and prostate cancer was also common among patients with first primary bladder cancer and penile cancer. Patients with second primary bladder cancer accounted for 56% of first primary ureteral cancer patients with SPCs. CONCLUSIONS: This study recommends close clinical follow-up, monitoring and appropriate interventions in patients with relevant FPCs for better screening and early diagnosis of SPCs.

Cytokines and chemokines involved in HLA-B27-positive ankylosing spondylitis-associated acute anterior uveitis.

Purpose: Acute anterior uveitis (AAU) is the most common extra-articular symptom of ankylosing spondylitis (AS). This study aims to reveal the cytokines and chemokines involved in the immunopathogenesis of human leucocyte antigen (HLA)-B27+ AS-associated AAU. Methods: Twenty-one HLA-B27+ AS-associated AAU patients and 21 healthy controls (HCs) were recruited for this study. Serum cytokine concentrations in all 42 subjects were determined by the Meso Scale Discovery (MSD) electrochemiluminescence method. In each sample, 34 cytokines, 10 chemokines, eight angiogenesis mediators, and four vascular injury mediators were measured. The differences in cytokine and chemokine concentrations were compared between the two groups. Results: Concentrations of serum IL-3, TNF-α, IL-6, IL-17D, IL-22, IP10/CXCL10, MIP-3α/CCL20, sFlt-1/VEGFR-1, CRP, and MCP-4/CCL13 were significantly higher in patients with HL-B27+ AS-associated AAU than in HCs (p < 0.05). In contrast, concentrations of serum IL-4, IL-8, MIP-1α/CCL3, Eotaxin-3/CCL26, PlGF, VEGF-C, and VEGF-D were significantly lower in patients with HL-B27+ AS-associated AAU than in HCs (p < 0.05). Conclusions: Significant differences were detected in the levels of several cytokines and chemokines in the serum of HLA-B27+ AS-associated AAU compared with HCs. Some novel differential cytokines and chemokines that have not been reported in other kinds of uveitis were also identified. These results reveal the underlying pathogenesis of HLA-B27+ AS-associated AAU and could potentially aid in clinical diagnosis.

lncRNA CRNDE promotes the proliferation and metastasis by acting as sponge miR-539-5p to regulate POU2F1 expression in HCC.

BACKGROUND: This article focuses on the roles and mechanism of lncRNA CRNDE on the progression of HCC. METHODS: We used qRT-PCR to detect the expression of lncRNA CRNDE in HCC cells, normal cells and clinical tissues. MTT assay, FCM analysis, Transwell migration and invasion assay were used to detect the effects of lncRNA CRNDE on cell viability, apoptosis, migration and invasion of HCC cells. The expression of apoptosis-related proteins Bcl-2, Bax, Cleaved Caspase 3, Cleaved Caspase 9, EMT epithelial marker E-cadherin and mesothelial marker Vimentin were analyzed by Western blot. Online prediction software was used to predict the binding sites between lncRNA CRNDE and miR-539-5p, or miR-539-5p and POU2F1 3'UTR. Dual luciferase reporter assay, qRT-PCR and RNA pulldown were used to detect target-relationship between lncRNA CRNDE and miR-539-5p. Dual luciferase reporter assay, qRT-PCR, Western blot and Immunofluorescence were used to detect target-relationship between miR-539-5p and POU2F1. qRT-PCR was used to detect the expression of miR-539-5p and POU2F1 in clinical tissues. Rescue experiments was used to evaluate the association among lncRNA CRNDE, miR-539-5p and POU2F1. Finally, we used Western blot to detect the effects of lncRNA CRNDE, miR-539-5p and POU2F1 on NF-κB and AKT pathway. RESULTS: lncRNA CRNDE was highly expressed in HCC cells and HCC tissues compared with normal cells and the corresponding adjacent normal tissues. lncRNA CRNDE promoted the cell viability, migration and invasion of HCC cells, while inhibited the apoptosis and promoted the EMT process of HCC cells. lncRNA CRNDE adsorbed miR-539-5p acts as a competitive endogenous RNA to regulate POU2F1 expression indirectly. In HCC clinical tissues, miR-539-5p expression decreased and POU2F1 increased compared with the corresponding adjacent normal tissues. lncRNA CRNDE/miR-539-5p/POU2-F1 participated the NF-κB and AKT pathway in HCC. CONCLUSION: lncRNA CRNDE promotes the expression of POU2F1 by adsorbing miR-539-5p, thus promoting the progression of HCC.

MiR-376a suppresses the proliferation and invasion of non-small-cell lung cancer by targeting c-Myc.

It has been reported that miR-376a is involved in the formation and progression of several types of cancer. However, the expression and function of miR-376a is still unknown in non-small cell lung carcinomas (NSCLC). In this study, the expression of miR-376a in NSCLC tissues and cell lines were examined by real-time PCR, the effects of miR-376a on cell proliferation, apoptosis and invasion were evaluated in vitro. Luciferase reporter assay was performed to identify the targets of miR-376a. The results showed that miR-376a was significantly downregulated in NSCLC tissues and cell lines. Restoration of miR-376a in NSCLC cell line A549 significantly inhibited cell proliferation, increased cell apoptosis and suppressed cell invasion, compared with control-transfected A549 cells. Luciferase reporter assay showed that c-Myc, an oncogene that regulating cell survival, angiogenesis and metastasis, was a direct target of miR-376a. Over-expression of miR-376a decreased the mRNA and protein levels of c-Myc in A549 cells. In addition, upregulation of c-Myc inhibited miR-376a-induced inhibition of cell proliferation and invasion in A549 cells. Therefore, our results indicate a tumor suppressor role of miR-376a in NSCLC by targeting c-Myc. miR-376a may be a promising therapeutic target for NSCLC.

The PI3K and AIB1 interaction is involved in estrogen treated breast cancer cells.

AIB1 was involved in the development and progression of breast cancer. Although it was found that AIB1 could be phosphorylated by some kinases including PI3K, the function of AIB1 and AKT interaction in breast cancer is not well defined. MCF-7 cells were transfected with pERE-Luc AKT and/or AIB1 plasmids, and then ERE luciferase activity in presence or absence of estrogen (E2) were measured. Plasmids containing PTEN and an PI3K inhibitor LY294002 were transfected into or treated cells to identify the interaction of PI3K/AKT and activation of AIB1, and examine their roles in cell cycle regulation. The AKT phosphorylation activity was evaluated by kinase assay using H2B as a substrate. The association between A1B1 and pS2 promoter was detected by the Chromatin Immunoprecipitation (ChIP) assay. AIB1 and AKT in the same complex were detected by Pull-down assay. IGF-1 can increase AIB1 recruitment to PS2 and enhance the ER-dependent transcription activity through the PI3K/AKT pathway. AIB1 associate with AKT to regulate cell cycle. The special relations concerning the AIB1 and AKT may arouse some new viewpoints for potential therapeutic targets in breast cancer.

Diagnostic serum biomarkers associated with ankylosing spondylitis.

Ankylosing spondylitis (AS) is an autoimmune rheumatic disease that mostly affects the axial skeleton. This study aimed to investigate reliable diagnostic serum biomarkers for AS. Serum samples were collected from 20 AS patients and 20 healthy controls (HCs) and analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The differential metabolites between the AS patients and HCs were profiled using univariate and multivariate statistical analyses. Pathway analysis and a heat map were also conducted. Random forest (RF) analysis and the least absolute shrinkage and selection operator (LASSO) were used to establish predictive and diagnostic models. After controlling the variable importance in the projection (VIP) value > 1 and false discovery rate (FDR) < 0.05, a total of 61 differential metabolites were identified from 995 metabolites, which exhibited significant differences in the pathway analysis and heat map between the AS patients and HCs. RF as a predictive model also identified differential metabolites with 95% predictive accuracy and a high area under the curve (AUC) of 1. A diagnostic model comprising nine metabolites (cysteinylglycine disulfide, choline, N6, N6, N6-trimethyllysine, histidine, sphingosine, fibrinopeptide A, glycerol 3-phosphate, 1-linoleoyl-GPA (18:2), and fibrinopeptide A (3-16)) was generated using LASSO regression, capable of distinguishing HCs from AS with a high AUC of 1. Our results indicated that the UPLC-MS/MS analysis method is a powerful tool for identifying AS metabolite profiles. We developed a nine-metabolites-based model serving as a diagnostic tool to separate AS patients from HCs, and the identified diagnostic biomarkers appeared to have a diagnostic value for AS.

Recent researches for dual Aurora target inhibitors in antitumor field.

Non-infectious and chronic diseases such as malignant tumors are now one of the main causes of human death. Its occurrence is a multi-factor, multi-step complex process with biological characteristics such as cell differentiation, abnormal proliferation, uncontrolled growth, and metastasis. It has been found that a variety of human malignant tumors are accompanied by over-expression and proliferation of Aurora kinase, which causes abnormalities in the mitotic process and is related to the instability of the genome that causes tumors. Therefore, the use of Aurora kinase inhibitors to target tumors is becoming a research hotspot. However, in cancer, because of the complexity of signal transduction system and the participation of different proteins and enzymes, the anticancer effect of selective single-target drugs is limited. After inhibiting one pathway, signal molecules can be conducted through other pathways, resulting in poor therapeutic effect of single-target drug treatment. Multi-target drugs can solve this problem very well. It can regulate the various links that cause disease at the same time without completely eliminating the relationship between the signal transmission systems, and it is not easy to cause drug resistance. Currently, studies have shown that Aurora dual-target inhibitors generated with the co-inhibition of Aurora and another target (such as CDK, PLK, JAK2, etc.) have better therapeutic effects on tumors. In this paper, we reviewed the studies of dual Aurora inhibitors that have been discovered in recent years.

HOXB5 promotes malignant progression in pancreatic cancer via the miR-6732 pathway.

Background: Homeobox B5 (HOXB5) is associated with the poor prognosis of various cancer types. However, the specific mechanism by which HOXB5 promotes the malignant progression of pancreatic cancer (PC) remains to be determined.Methods: The Cancer Genome Atlas database indicated HOXB5 expression level correlated to PC prognosis. The biological functions of HOXB5 was confirmed by colony formation, migration, and invasion assays. The effects of HOXB5 on the expression of cancer stem cell and epithelial-mesenchymal transition markers were evaluated. The downstream target of HOXB5 was miR-6723, which was detected by transcriptional assay. A xenograft tumor model was established in nude mice for the assessment of the role of HOXB5 in tumor growth and metastasis.Results: PC tissues had higher HOXB5 expression levels than noncancerous tissues, and high HOXB5 expression was significantly associated with poor PC prognosis. HOXB5 knockdown suppressed clone formation and the proliferation, invasion, and migration of PC cells in vitro. Conversely, these activities were enhanced by HOXB5 overexpression. The HOXB5 that bound two synergy motifs regulated miR-6723 expression and contributed to PC malignant progression. The role of HOXB5 in promoting tumor growth and metastasis was verified in vivo. Further investigation revealed that Twist1 and Zeb1 expression levels were increased by HOXB5.Conclusions: HOXB5 overexpression was significantly correlated with poor PC prognosis. HOXB5 accelerated the malignant progression of PC by up-regulating miR-6723, which afforded PC cells stem-like properties and facilitated the epithelial-mesenchymal transition of PC cells.

Up-regulation of SNHG6 activates SERPINH1 expression by competitive binding to miR-139-5p to promote hepatocellular carcinoma progression.

We aimed to assess the roles of small nucleolar RNA host gene 6 (SNHG6) in hepatocellular carcinoma (HCC) progression, and establish the lncRNA-miRNA-mRNA regulation mechanism for HCC therapy. SNHG6 is one of the host genes in small nucleolar RNAs (snoRNAs), which make a difference in the development of human cancers. SERPINH1 is a gene encoding a member of the serpin superfamily of serine proteinase inhibitors with miRNA predicted by TargetScan and DIANA Tools. SNHG6, serpin family H member 1 (SERPINH1) and miR-139-5p expression levels in HCC tissues and cells were determined by quantitative real-time PCR (qRT-PCR). Migration and invasion of HCC cells were measured by transwell assay. Cell cycle analysis was determined by using flow cytometry. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and colony formation assay were performed for cell viability analysis. The expression of SERPINH1 was detected by qRT-PCR and western blot. Dual-luciferase reporter gene assay was conducted to identify the targeted relationship between miR-139-5p and SNHG6, as well as SERPINH1 and miR-139-5p. The positive regulation between SNHG6 and SERPINH1 was demonstrated in this study. In contrast, miR-139-5p was significantly down-regulated in HCC cells, the inhibition of miR-139-5p promotes the proliferation of HCC cells, and accelerated the cell cycle of HCC cells. Our study demonstrated the co-expression of SNHG6 and SERPINH1 in HCC cells for the first time, which revealed that SNHG6 could serve as a novel oncogene for the HCC therapy by its regulation.

Novel compound heterozygous PKHD1 mutations cause autosomal recessive polycystic kidney disease in a Han Chinese family.

Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary fibrocystic disease that primarily involves the kidneys and hepatobiliary tract. The polycystic kidney and hepatic disease 1 (PKHD1) gene is the only gene implicated in ARPKD. The present study aimed to identify PKHD1 mutations causing ARPKD in a Chinese family. A couple that underwent prenatal genetic diagnosis for ARPKD and their families were recruited for the present study. Genomic DNA was collected from the amniotic fluid of the fetus (proband) and from peripheral blood of all other available family members. Targeted exome sequencing was performed on the couple and the proband, followed by direct Sanger sequencing on other family members and normal controls to confirm candidate pathogenic variants. Two novel compound heterozygous mutations in the PKHD1 gene were identified as causative in the proband, including maternally inherited c.2876C>T (p.Ser959Phe) and paternally inherited c.5772C>A (p.Phe1924Leu). Each mutation was found to co­segregate with the ARPKD phenotype in the family. Other family members either carried one of the two mutations or lacked both mutations, while the mutations were not found in 576 ethnically matched normal controls. Therefore, two novel compound heterozygous PKHD1 mutations were implicated in causing ARPKD in a Han Chinese family. The results expand the mutation spectrum of PKHD1 that leads to ARPKD, which may improve genetic counseling and prenatal diagnosis for families with ARPKD.

miR-34a Inhibits Cell Proliferation by Targeting SATB2 in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of malignancy of the liver and has been reported as the third most frequent cause of cancer associated death worldwide. Accumulating evidence showed that the expression of miR-34a was abnormal in HCC patients; however, the role of miR-34a in HCC is not clear. In this study, we have observed low expression of the miR-34a in both HCC tissues and hepatoma cell line as compared to normal control. Further to investigate the role of miR-34a in HCC development, HepG2 cells were transfected with miR-34a mimic. Following transfection, miR-34a expression was significantly increased, which further repressed proliferation of HepG2 cells. Bioinformatics, Luciferase Reporter, RT-qPCR, and western blotting assays indicated that special AT-rich sequence-binding protein-2 (SATB2) is a direct target of miR-34a in HCC cells. There was a negative correlation between the expression levels of SATB2 and miR-34a. Investigation into the molecular mechanism indicated that miR-34a regulated cell proliferation through inhibiting SATB2. Therefore, the results of the present study may improve understanding regarding the role of miR-34a in regulating cell proliferation and contribute to the development of novel therapy of HCC.

miR-16 inhibits hyperoxia-induced cell apoptosis in human alveolar epithelial cells.

The identification and development of novel therapeutic strategies for acute lung injury is urgently required. It has been previously demonstrated that microRNA (miR)­16 suppresses the level of transforming growth factor (TGF)­ß in acute lung injury (ALI). Therefore, the present study investigated the role of miR­16 in the phenotype, cell proliferation and apoptosis, and the involvement of TGF­ß/Smad family member 2 (Smad2) and JAK/signal transducer and activator of transcription (STAT)3 signaling, of primary human alveolar type II epithelial cells (AECII). Following transfection with miR­16 mimics, AECII cells were exposed to hyperoxia for 24 h. Subsequently, immunofluorescence staining of surfactant protein­A (SP­A) was performed, and cell proliferation and apoptosis were investigated by Cell Counting Kit­8 assays and annexin V­fluorescein isothiocyanate/propidium iodide staining, respectively. Furthermore, the expression levels of miR­16, TGF­ß, Smad2, phosphorylated­Smad2, JAK and STAT3 were detected by western blotting and/or reverse transcription­quantitative polymerase chain reaction. The results demonstrated that miR­16 levels and SP­A fluorescence were markedly inhibited by hyperoxia. Furthermore, transfection of AECII cells with miR­16 mimics increased SP­A fluorescence in hyperoxia­treated AECII cells, significantly reversed hyperoxia­induced reductions in cell proliferation and inhibited hyperoxia­induced apoptosis. Finally, miR­16 mimics modulated the mRNA and protein expression of components of the TGF­ß/Smad2 and JAK/STAT3 pathways in AECII cells following hyperoxia. In conclusion, the results of the present study indicate that overexpression of miR­16 may exert a protective effect in AECII cells against cell apoptosis and ALI, which may be associated with TGF­ß/Smad2 and JAK/STAT3 signaling pathways. This may also represent a promising target for novel therapeutic strategies for acute lung injury.

Lin28B over-expression mediates the repression of let-7 by hepatitis B virus X protein in hepatoma cells.

The Let-7 microRNA (miRNA) family is frequently downregulated in multiple human tumors, including hepatocellular carcinoma (HCC). Our previous report demonstrated that hepatitis B virus X protein (HBx) suppressed the expression of let-7 in HepG2 hepatoma cells. However, the underlying mechanisms were not elucidated. Lin28B is known to negatively regulate the maturation of let-7, and this prompted us to determine whether HBx acts through Lin28B to suppress let-7. Real-time reverse-transcription polymerase chain reaction (qRT-PCR) was performed to examine let-7 expression before and after treatment with c-Myc-and Lin28B-specific siRNAs in HepG2 cells stably/transiently transfected with HBx. mRNA and protein analyses were employed to determine the correlation of HBx, c-Myc and Lin28B in HCC tissues and cells. Cell cycle and proliferation assays were performed to delineate the consequences of Lin28B repression in HepG2 cells expressing HBx. Lin28B was overexpressed in HBx-transfected cells and HBV-infected liver tissues. HBx-c-Myc-Lin28B axis mediated the repression of let-7 in HepG2 cells. Reduced expression of Lin28B inhibited the growth and cell cycle progression of HepG2 cells by derepressing let-7 and repressing c-Myc. There was not only a preliminary HBx-c-Myc-Lin28B-let-7 pathway but also another possible double-negative feedback loop between c-Myc/Lin28B and let-7 in HepG2 cells transfected with HBx, which together induced the deregulation of let-7. Lin28B has the potential to be a novel molecular target in the treatment of HBV(+) HCC.