Publications by authors named "Jiekai Yu"

56 Publications

Targeting the NAD salvage pathway suppresses APC mutation-driven colorectal cancer growth and Wnt/β-catenin signaling via increasing Axin level.

Cell Commun Signal 2020 01 31;18(1):16. Epub 2020 Jan 31.

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310009, Hangzhou, China.

Background: The role and mechanism of the nicotinamide adenine dinucleotide (NAD) salvage pathway in cancer cell proliferation is poorly understood. Nicotinamide phosphoribosyltransferase (NAMPT), which converts nicotinamide into NAD, is the rate-limiting enzyme in the NAD salvage pathway. Here, we assessed the role of NAMPT in the proliferation of colorectal cancer.

Methods: Real-time PCR, immunohistochemistry, western blotting, and analyses of datasets from Oncomine and Gene Expression Omnibus were conducted to assess the expression of NAMPT at the mRNA and protein levels in colorectal cancer. The Kaplan Meier plotter online tool was used to evaluate the prognostic role of NAMPT. Knockdown of NAMPT was performed to assess the role of NAMPT in colorectal cancer cell proliferation and tumorigenesis both in vitro and in vivo. Overexpression of NAMPT was used to evaluate impact of NAMPT on colorectal cancer cell proliferation in vitro. NAD quantitation, immunofluorescence, dual luciferase assay and western blot were used to explore the mechanism of colorectal cancer proliferation. Transwell migration and invasion assays were conducted to assess the role of NAMPT in cell migration and invasion abilities of colorectal cancer cells.

Results: Our study indicated that the inhibition of NAMPT decreased proliferation capacity of colorectal cancer cells both in vitro and in vivo. Conversely, overexpression of NAMPT could promote cell proliferation in vitro. NAMPT inhibition induced β-catenin degradation by increasing Axin expression levels; this resulted in the inhibition of Wnt/β-catenin signaling and cell proliferation in colorectal cancer. The addition of nicotinamide mononucleotide, the enzymatic product of NAMPT, effectively reversed β-catenin protein degradation and inhibited growth. Similarly, the knockdown of Axin also decreased the cell death induced by the inhibition of NAMPT. In addition, we showed that colorectal cancer tissues harbored significantly higher levels of NAMPT than the levels harbored by paired normal tissues, especially in colorectal cancer stages I and II. And the overexpression of NAMPT was associated with unfavorable survival results.

Conclusions: Our findings reveal that NAMPT plays an important role in colorectal cancer proliferation via Wnt/β-catenin pathway, which could have vital implications for the diagnosis, prognosis and treatment of colorectal cancer.
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http://dx.doi.org/10.1186/s12964-020-0513-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995173PMC
January 2020

8-Hydroxyguanosine as a possible RNA oxidative modification marker in urine from colorectal cancer patients: Evaluation by ultra performance liquid chromatography-tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Jan 9;1136:121931. Epub 2019 Dec 9.

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, Zhejiang 310009, China.

Oxidative RNA damage has been found to be associated with a variety of diseases, and 8-hydroxyguanosine (8-OHG) is a typical marker of oxidative modification of RNA. This guanosine modification is an emerging biomarker for disease detection and determination of 8-OHG in human urine is favored because it is noninvasive to patients. However, due to its poor ionization efficiency in mass spectrometry and trace amount in urine, accurate quantification of this modified nucleoside is still challenging. Herein, a rapid, accurate, sensitive and robust method using solid-phase extraction (SPE) combined with isotope dilution ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed for detection of this oxidative RNA modification in human urine. The limit of detection can reach 1.5 fmol and the method exhibits good precision on intra-day (1.8-3.3%) and inter-day (0.6-1.2%) analyses. Satisfactory recovery (87.5-107.2%) at three spiked levels was achieved by using HLB cartridge for urine pretreatment. Using this method, we quantified 8-OHG in urine from 65 colorectal cancer (CRC) patients and 76 healthy volunteers. The measured level of urinary 8-OHG for CRC patients and healthy controls is 1.91 ± 0.63 nmol/mmol creatinine and 1.33 ± 0.35 nmol/mmol creatinine, respectively. We found the content of 8-OHG in urine was raised in CRC patients patients, implying this oxidative RNA modification marker could act as a potential noninvasive indicator for early screening of CRC. In addition, this study will make contributions to the investigations of the influences of oxidative stress on the formation and development of CRC.
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http://dx.doi.org/10.1016/j.jchromb.2019.121931DOI Listing
January 2020

High-risk Stage III colon cancer patients identified by a novel five-gene mutational signature are characterized by upregulation of IL-23A and gut bacterial translocation of the tumor microenvironment.

Int J Cancer 2020 04 27;146(7):2027-2035. Epub 2019 Nov 27.

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

The heterogeneities of colorectal cancer (CRC) lead to staging inadequately of patients' prognosis. Here, we performed a prognostic analysis based on the tumor mutational profile and explored the characteristics of the high-risk tumors. We sequenced 338 colorectal carcinomas as the training dataset, constructed a novel five-gene (SMAD4, MUC16, COL6A3, FLG and LRP1B) prognostic signature, and validated it in an independent dataset from The Cancer Genome Atlas (TCGA). Kaplan-Meier and Cox regression analyses confirmed that the five-gene signature is an independent predictor of recurrence and prognosis in patients with Stage III colon cancer. The mutant signature translated to an increased risk of death (hazard ratio = 2.45, 95% confidence interval = 1.15-5.22, p = 0.016 in our dataset; hazard ratio = 4.78, 95% confidence interval = 1.33-17.16, p = 0.008 in TCGA dataset). RNA and bacterial 16S rRNA sequencing of high-risk tumors indicated that mutations of the five-gene signature may lead to intestinal barrier integrity, translocation of gut bacteria and deregulation of immune response and extracellular related genes. The high-risk tumors overexpressed IL23A and IL1RN genes and enriched with cancer-related bacteria (Bacteroides fragilis,Peptostreptococcus, Parvimonas, Alloprevotella and Gemella) compared to the low-risk tumors. The signature identified the high-risk group characterized by gut bacterial translocation and upregulation of interleukins of the tumor microenvironment, which was worth further researching.
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http://dx.doi.org/10.1002/ijc.32775DOI Listing
April 2020

Screening and identification of non-inflammatory specific protein markers in Wilms' tumor tissues.

Arch Biochem Biophys 2019 11 21;676:108112. Epub 2019 Sep 21.

Department of Surgery, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, Henan, China. Electronic address:

Wilms' tumor is one of the most common malignancies in children, and early diagnosis is critical for its subsequent treatment and prognosis. Our previous study employed proteomics to investigate protein markers in the serum of Wilms' tumor children. The present study aimed to identify specific protein markers in Wilms' tumor. Proteomic comparison of Wilms' tumor with normal kidney tissues and the sera of systemic inflammatory response syndrome (SIRS) controls was performed. Surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF-MS) identified a protein with m/z 8350 as specific to Wilms' tumor. The target protein was purified using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and identified as profilin-1 by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF). Its expression was validated using real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Our data identify profilin-1 as a potential protein marker for Wilms' tumor and demonstrate the feasibility of the above procedures for screening and identification of tumor-specific protein markers.
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http://dx.doi.org/10.1016/j.abb.2019.108112DOI Listing
November 2019

Serum protein expression patterns in detecting a new viral protein in HBeAg-negative chronic hepatitis B.

J Viral Hepat 2019 07;26 Suppl 1:90-97

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

We analysed the changes in viral protein expression in HBeAg-negative chronic hepatitis B (CHB). In total, 160 samples were obtained from individuals infected by hepatitis B virus (HBV) and divided into four groups. Group A included 71 cases of hepatitis B e antigen (HBeAg)-negative CHB, Group B included 58 cases of inactive seroconverters and Group C included 31 cases of HBeAg-positive CHB. Group D included 22 normal healthy individuals as a control. All serum samples were examined using surface enhance laser desorption/ionization time of flight-mass spectrometry (SELDI-TOF-MS). The results indicated that a peak with 4140 m/z increased markedly in Group A at 1295.55 ± 745.87, which was significantly different from that in Group B at 896.99 ± 534.86 (P = 0.013). This peak indicated a close relationship with HBV DNA replication and may contribute to pathogenesis of HBeAg-negative chronic hepatitis.
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http://dx.doi.org/10.1111/jvh.13166DOI Listing
July 2019

Acid Sphingomyelinase regulates the localization and trafficking of palmitoylated proteins.

Biol Open 2019 10 15;8(10). Epub 2019 Oct 15.

Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV 89154-4003, USA

In human, loss of Acid Sphingomeylinase (ASM/SMPD1) causes Niemann-Pick Disease, type A. ASM hydrolyzes sphingomyelins to produce ceramides but protein targets of ASM remain largely unclear. Our mass-spectrometry-based proteomic analyses have identified >100 proteins associated with the ASM-dependent, detergent-resistant membrane microdomains (lipid rafts), with >60% of these proteins being palmitoylated, including SNAP23, Src-family kinases Yes and Lyn, and Ras and Rab family small GTPases. Inactivation of ASM abolished the presence of these proteins in the plasma membrane, with many of them trapped in the Golgi. While palmitoylation inhibitors and palmitoylation mutants phenocopied the effects of ASM inactivation, we demonstrated that ASM is required for the transport of palmitoylated proteins, such as SNAP23 and Lyn, from the Golgi to the plasma membrane without affecting palmitoylation directly. Importantly, ASM delivered extracellularly can regulate the trafficking of SNAP23 from the Golgi to the plasma membrane. Our studies suggest that ASM, acting at the plasma membrane to produce ceramides, regulates the localization and trafficking of the palmitoylated proteins.
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http://dx.doi.org/10.1242/bio.040311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826292PMC
October 2019

Zyxin as a potential cancer prognostic marker promotes the proliferation and metastasis of colorectal cancer cells.

J Cell Physiol 2019 Jan 29. Epub 2019 Jan 29.

Department of Medical Oncology, (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences) The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Colorectal cancer (CRC) is a leading cause of cancer death. This study was conducted to investigate the functions and mechanisms of Zyxin (ZYX) in CRC. Multiomics analysis associated ZYX with CRC metastasis. ZYX expression levels were increased in human CRC tissues and related to shorter recurrence-free survival. Knockdown of ZYX expression resulted in inhibition of cell growth, invasion, and migration in vitro and in vivo. Comprehensive analysis of gene microarray analysis showed that ZYX may activate the pathway of NUPR1 and JNK, inhibit CST5, regulate focal adhesion (FA), and affect epithelial-mesenchymal transition in CRC cells. Results of gene microarray and membrane protein isobaric tags with relative and absolute quantitation labeling mass spectrometry found ten differentially expressed genes, which were associated with ZYX activity. Furthermore, real-time polymerase chain reaction was used to validate the expression patterns of selected genes in the integrative analysis. Taken together, our findings provide the first evidence that decreased expression level of ZYX impairs CRC cell proliferation and metastasis probably via the FA pathway.
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http://dx.doi.org/10.1002/jcp.28236DOI Listing
January 2019

Proteolysis of methylated SOX2 protein is regulated by L3MBTL3 and CRL4 ubiquitin ligase.

J Biol Chem 2019 01 15;294(2):476-489. Epub 2018 Nov 15.

From the Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Nevada 89154 and

SOX2 is a dose-dependent master stem cell protein that controls the self-renewal and pluripotency or multipotency of embryonic stem (ES) cells and many adult stem cells. We have previously found that SOX2 protein is monomethylated at lysine residues 42 and 117 by SET7 methyltransferase to promote SOX2 proteolysis, whereas LSD1 and PHF20L1 act on both methylated Lys-42 and Lys-117 to prevent SOX2 proteolysis. However, the mechanism by which the methylated SOX2 protein is degraded remains unclear. Here, we report that L3MBTL3, a protein with the alignant-rain-umor (MBT) methylation-binding domain, is required for SOX2 proteolysis. Our studies showed that L3MBTL3 preferentially binds to the methylated Lys-42 in SOX2, although mutation of Lys-117 also partially reduces the interaction between SOX2 and L3MBTL3. The direct binding of L3MBTL3 to the methylated SOX2 protein leads to the recruitment of the CRL4 ubiquitin E3 ligase to target SOX2 protein for ubiquitin-dependent proteolysis. Whereas loss of either LSD1 or PHF20L1 destabilizes SOX2 protein and impairs the self-renewal and pluripotency of mouse ES cells, knockdown of L3MBTL3 or DCAF5 is sufficient to restore the protein levels of SOX2 and rescue the defects of mouse ES cells caused by LSD1 or PHF20L1 deficiency. We also found that retinoic acid-induced differentiation of mouse ES cells is accompanied by the enhanced degradation of the methylated SOX2 protein at both Lys-42 and Lys-117. Our studies provide novel insights into the mechanism by which the methylation-dependent degradation of SOX2 protein is controlled by the L3MBTL3-CRL4 ubiquitin ligase complex.
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http://dx.doi.org/10.1074/jbc.RA118.005336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333883PMC
January 2019

Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4 ubiquitin ligase.

Nat Commun 2018 04 24;9(1):1641. Epub 2018 Apr 24.

Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV89154, USA.

Many non-histone proteins are lysine methylated and a novel function of this modification is to trigger the proteolysis of methylated proteins. Here, we report that the methylated lysine 142 of DNMT1, a major DNA methyltransferase that preserves epigenetic inheritance of DNA methylation patterns during DNA replication, is demethylated by LSD1. A novel methyl-binding protein, L3MBTL3, binds the K142-methylated DNMT1 and recruits a novel CRL4 ubiquitin ligase to degrade DNMT1. Both LSD1 and PHF20L1 act primarily in S phase to prevent DNMT1 degradation by L3MBTL3-CRL4. Mouse L3MBTL3/MBT-1 deletion causes accumulation of DNMT1 protein, increased genomic DNA methylation, and late embryonic lethality. DNMT1 contains a consensus methylation motif shared by many non-histone proteins including E2F1, a key transcription factor for S phase. We show that the methylation-dependent E2F1 degradation is also controlled by L3MBTL3-CRL4. Our studies elucidate for the first time a novel mechanism by which the stability of many methylated non-histone proteins are regulated.
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http://dx.doi.org/10.1038/s41467-018-04019-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915600PMC
April 2018

Identification of Kininogen 1 as a Serum Protein Marker of Colorectal Adenoma in Patients with a Family History of Colorectal Cancer.

J Cancer 2018 8;9(3):540-547. Epub 2018 Mar 8.

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

The serum protein markers of colorectal adenoma in patients with a family history of colorectal cancer have been rarely reported. Serum samples from colorectal adenoma patients with or without a family history of colorectal cancer and healthy controls were profiled using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). The model to distinguish colorectal adenoma patients with a family history of colorectal cancer from atypical hereditary colorectal families (CRA-H) and sporadic colorectal adenoma patients without a family history of colorectal cancer (CRA-S) was established with 85.0% accuracy. The model distinguishing CRA-H from healthy individuals was established with 90.0% specificity and 86.7% sensitivity. Additionally, five peaks (2202, 5821, 3260, 2480, and 2218) showing differential expression in advanced colorectal adenoma patients with a family history of colorectal cancer were selected. The protein Kininogen 1 (KNG1) was identified in colorectal adenoma patients and validated using Western Blotting. KNG1 may be a biomarker for colorectal adenoma patients with a family history of colorectal cancer.
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http://dx.doi.org/10.7150/jca.22405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845484PMC
March 2018

Beyond cancer genes: colorectal cancer as robust intrinsic states formed by molecular interactions.

Open Biol 2017 11;7(11)

Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China

Colorectal cancer (CRC) has complex pathological features that defy the linear-additive reasoning prevailing in current biomedicine studies. In pursuing a mechanistic understanding behind such complexity, we constructed a core molecular-cellular interaction network underlying CRC and investigated its nonlinear dynamical properties. The hypothesis and modelling method has been developed previously and tested in various cancer studies. The network dynamics reveal a landscape of several attractive basins corresponding to both normal intestinal phenotype and robust tumour subtypes, identified by their different molecular signatures. Comparison between the modelling results and gene expression profiles from patients collected at the second affiliated hospital of Zhejiang University is presented as validation. The numerical 'driving' experiment suggests that CRC pathogenesis may depend on pathways involved in gastrointestinal track development and molecules associated with mesenchymal lineage differentiation, such as Stat5, BMP, retinoic acid signalling pathways, Runx and Hox transcription families. We show that the multi-faceted response to immune stimulation and therapies, as well as different carcinogenesis and metastasis routes, can be straightforwardly understood and analysed under such a framework.
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http://dx.doi.org/10.1098/rsob.170169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717345PMC
November 2017

Identification of MST1 as a potential early detection biomarker for colorectal cancer through a proteomic approach.

Sci Rep 2017 10 27;7(1):14265. Epub 2017 Oct 27.

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.

Colorectal cancer (CRC) is a common malignant neoplasm worldwide. It is important to identify new biomarkers for the early detection of CRC. In this study, magnetic beads and the Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) platform were used to analyse CRC and healthy control (HC) serum samples. The CRC diagnosis pattern was established to have a specificity of 94.7% and sensitivity of 92.3% in a blind test. The candidate biomarker serine/threonine kinase 4 (STK4, also known as MST1) was identified by Tandem mass spectrometry (MS/MS) and verified with western blotting and enzyme-linked immunosorbent assay (ELISA). The results indicated that there was a higher concentration of MST1 in HC subjects than stage I CRC patients for the early detection of CRC and a lower concentration in stage IV patients than in other CRC patients. The sensitivity and specificity of MST1 combined with carcinoembryonic antigen (CEA) and faecal occult blood test (FOBT) in diagnosis of colorectal cancer were 92.3% and 100%, respectively. Additionally, low MST1 expression was associated with the poor prognosis. These results illustrate that MST1 is a potential biomarker for early detection, prognosis and prediction of distant metastasis of CRC.
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http://dx.doi.org/10.1038/s41598-017-14539-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660227PMC
October 2017

CLCA1 suppresses colorectal cancer aggressiveness via inhibition of the Wnt/beta-catenin signaling pathway.

Cell Commun Signal 2017 10 3;15(1):38. Epub 2017 Oct 3.

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, China), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Background: Chloride channel accessory 1 (CLCA1) belongs to the calcium-sensitive chloride conductance protein family, which is mainly expressed in the colon, small intestine and appendix. This study was conducted to investigate the functions and mechanisms of CLCA1 in colorectal cancer (CRC).

Methods: The CLCA1 protein expression level in CRC patients was evaluated by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and western blotting analysis. Using CRISPR/Cas9 technology, CLCA1-upregulated (CLCA1-ACT) and CLCA1-knockout cells (CLCA1-KO), as well as their respective negative controls (CLCA1-ACT-NC and CLCA1-KO-NC), were constructed from the SW620 cell line. Cell growth and metastatic ability were assessed both in vitro and in vivo. The association of CLCA1 with epithelial-mesenchymal transition (EMT) and other signaling pathways was determined by western blotting assays.

Results: The expression level of CLCA1 in CRC tissues was significantly decreased compared with that in adjacent normal tissue (P< 0.05). Meanwhile, the serum concentration of CLCA1 in CRC patients was also significantly lower when compared with that of healthy controls (1.48 ± 1.06 ng/mL vs 1.06 ± 0.73 ng/mL, P = 0.0018). In addition, CLCA1 serum concentration and mRNA expression level in CRC tissues were inversely correlated with CRC metastasis and tumor stage. Upregulated CLCA1 suppressed CRC growth and metastasis in vitro and in vivo, whereas inhibition of CLCA1 led to the opposite results. Increased expression levels of CLCA1 could repress Wnt signaling and the EMT process in CRC cells.

Conclusions: Our findings suggest that increased expression levels of CLCA1 can suppress CRC aggressiveness. CLCA1 functions as a tumor suppressor possibly via inhibition of the Wnt/beta-catenin signaling pathway and the EMT process.
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http://dx.doi.org/10.1186/s12964-017-0192-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627483PMC
October 2017

Discriminating patients with early-stage breast cancer from benign lesions by detection of oxidative DNA damage biomarker in urine.

Oncotarget 2017 Aug 12;8(32):53100-53109. Epub 2017 May 12.

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.

Breast cancer is one of the most commonly diagnosed and death-related cancers in women worldwide. Mammography is routinely used for screening and invasive examinations such as painful tissue biopsies were recommended for patients with abnormal screening outcomes. However, a considerable proportion of these cases turn out to be benign lesions. Thus, novel non-invasive approach for discriminating breast cancer from benign lesions is desirable. Herein, we applied a high-throughput ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) analysis to determine the oxidative DNA damage biomarker, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine samples from 60 patients with early-stage breast cancer (stage I, II), 51 patients with benign breast diseases and 73 healthy volunteers. We demonstrated that the concentration of urinary 8-oxodG in patients with early-stage breast cancer was significantly higher not only than that in healthy controls, but also than that in patients with benign breast diseases, whereas no significant difference of urinary 8-oxodG level was observed between benign breast diseases group and healthy control group. Moreover, there was significant difference between early-stage breast cancer group and non-cancerous group which consisted of benign breast diseases patients and healthy controls. Besides, logistic regression analysis and receiver operator characteristic (ROC) curve analysis were also performed. Our findings indicate that the marked increase of 8-oxodG in urine may serve as a potential biomarker for the risk estimation, early screening and detection of breast cancer, particularly for discriminating early-stage breast cancer from benign lesions.
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http://dx.doi.org/10.18632/oncotarget.17831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581095PMC
August 2017

Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer.

Breast Cancer Res Treat 2017 Dec 20;166(3):865-873. Epub 2017 Aug 20.

Department of Surgical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jie-Fang Rd, Hangzhou, 310009, Zhejiang, China.

Background: PALB2 (Partner and Localizer of BRCA2) is recently recognized as a breast cancer predisposition gene. Germline loss-of-function mutations in PALB2 lead to increased breast cancer risk. Since the germline mutation frequency of PALB2 is much less than BRCA1/2, the distinct mutation spectrum of PALB2 is still obscure. To verify the utility of PALB2 genetic testing in Chinese population, we assessed the mutational frequency, spectrum, and predictors of the PALB2 gene in a sequential series of Chinese breast cancer patients from our Research DNA Bank.

Methods: We examined breast cancer samples (n = 2279) collected from 2000 through 2016 from Chinese patients who agreed to participate in research DNA banking. To identify the mutations, complete coding sequence and intron-exon boundaries of PALB2 were screened with Next-Generation Sequencing. Personal and family histories were synchronously collected for mutation identification.

Results: Among the 2279 breast cancer patients, 305 patients were familial breast cancer cases and the rest 1967 patients were sporadic breast cancer cases. PALB2 loss-of-function mutation carriers accounted for 1.31% (n = 4) and 0.56% (n = 11) in familial and sporadic breast cancer cohort separately. In total, 30 missenses, four nonsenses, three frameshifts, three splicings, and one inframe deletions of PALB2 were identified in this study. Among the deleterious mutations, PALB2 c.1744C>T, c.2748+1G>A, c.2749-1G>C, c.3114-1G>A were newly identified in sporadic breast cancer, and c.3271delC newly found in familial breast cancer. Based on in silico analysis, we found two potentially damaging missense variants with high frequency: c.1213C>G, c.3054G>C, and classified six new potentially damaging missense variants.

Conclusions: Our data presented the germline mutation status of PALB2 in Chinese breast cancer patients, suggesting that loss-of-function germline mutations of PALB2 are important in both familial and sporadic breast cancer. Clinically, these data may be helpful in genetic counseling of breast cancer patients with PALB2 germline mutation.
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http://dx.doi.org/10.1007/s10549-017-4425-zDOI Listing
December 2017

Detection and identification of serum protein peak at 6648 m/z as a novel indicator in breast cancer based on mass spectrometry.

Discov Med 2017 05;23(128):283-294

Department of Pediatric Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

Breast cancer (BC) is the second-leading cause of cancer mortality after lung cancer in women owing partly to a lack of specific and sensitive tests for early screening and monitoring. The detection of novel specific BC serum indicators for screening purposes is an essential clinical need. A total of 437 serum specimens from 310 BC patients that were divided into mining and testing sets were collected in this study. In contrast with the conventional BC indicators through receiver operating characteristic, survival and hazard function curves, and multivariate Cox regression analyses, we intended to hunt for stable protein indicators from serum specimens and identify their diagnostic and prognostic potential for BC. We identified a unique serum peptide located at 6648 Da originated from apoC-III with a validated correlation with BC tumorigenesis with confirmation in a substantive testing set and minimization of systematic bias by pre-analytical parameters. We found that the diagnostic efficacy of this peptide is better than the present conventional BC diagnostic indicators either alone or in combination with conventional indicators in distinguishing BC patients from control volunteers. Moreover, this peptide denotes a stronger prognostic factor for BC patients than conventional indicators. In light of these findings, we speculate that this peptide is a potential diagnostic and prognostic indicator and a supplement to conventional indicators in monitoring BC. The detection of this peptide located at 6648 Da in sera could enhance early screening and assessment of the postoperative survival opportunity for BC patients.
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May 2017

Identification of differentially expressed inflammatory factors in Wilms tumors and their association with patient outcomes.

Oncol Lett 2017 Jul 26;14(1):687-694. Epub 2017 May 26.

Department of Pediatric Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.

The present study aimed to identify differentially expressed inflammatory factors observed in Wilms tumors (WT), and to investigate the association of these factors with clinical stage, pathological type, lymph node metastasis and vascular involvement of WT. Surface-enhanced laser desorption/ionization-time of flight mass spectrometry was performed to screen differentially expressed proteins among WT and normal tissue pairs. Upregulated proteins in WT were separated and purified by solid phase extraction and Tricine SDS-PAGE, respectively. Following in-gel digestion, the peptide mixture was subjected to liquid chromatography mass spectrometry to identify proteins on the basis of their amino acid sequences. Immunohistochemistry was used to confirm the expression of differentially expressed inflammatory proteins. Of the proteins that were upregulated in WT, two proteins with mass/charge (m/z) ratio of 12,138 and 13,462 were identified as macrophage migration inhibitory factor (MIF) and C-X-C motif ligand 7 (CXCL7) chemokine, respectively. The expression of these two proteins was increased in WT compared with adjacent normal tissues and normal renal tissues, and increased with increasing clinical stage. In addition, their expression was significantly increased in patients with unfavorable pathological type, lymph node metastasis and vascular involvement compared with the groups with favorable type, and without lymph node metastasis or vascular involvement (P<0.05). Increased pro-inflammatory MIF and CXCL7 expression in WT is closely associated with the clinical stage, pathological type, lymph node metastasis and vascular involvement, and may represent biomarkers for the clinical diagnosis of WT.
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http://dx.doi.org/10.3892/ol.2017.6261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494663PMC
July 2017

Inflammation factors in hepatoblastoma and their clinical significance as diagnostic and prognostic biomarkers.

J Pediatr Surg 2017 Sep 1;52(9):1496-1502. Epub 2017 Feb 1.

Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, PR China. Electronic address:

Purpose: The aims of this study were to identify inflammation factors in hepatoblastoma tissue that correlated with different clinical characteristics, and to explore the probability as predictive biomarkers for diagnosis and prognosis.

Methods: SELDI-TOF-MS was performed to screen protein peaks that were significantly highly expressed in tumor tissue compared with adjacent liver tissue. After removing proteins larger than 30kDa, the targeted peaks were separated by solid phase extraction and tricine-SDS-PAGE. Protein fragments produced by in-gel digestion were identified by LC-MS/MS. Immunohistochemical assays further confirmed these results. Overall survival curves were graphed by Kaplan-Meier method and multivariate analysis was performed by Cox proportional hazards regression model.

Results: Three protein peaks (m/z 12,138, m/z 13,462, and m/z 15,120) that were significantly upregulated in the tumor tissue were identified as macrophage migration inhibitory factor (MIF), chemokine (C-X-C motif) ligand 7 (CXCL7), and interleukin 25 (IL-25). These factors were closely related to clinical stage, lymph node metastasis, vascular invasion and serum AFP level. High expression of each inflammatory marker indicated poor prognosis. Multivariate analysis suggested that MIF, CXCL7, and IL-25 were prognostic factors independent of patient sex, age and tumor histological type.

Conclusions: MIF, CXCL7, and IL-25 might be considered as effective inflammation factors for diagnosis and prognosis of hepatoblastoma and as potential novel treatment targets through inhibition of inflammatory function.

Type Of Study: Prognosis study LEVEL OF EVIDENCE: Level I.
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http://dx.doi.org/10.1016/j.jpedsurg.2017.01.059DOI Listing
September 2017

Identification of proteins associated with pediatric bilateral Wilms tumor.

Oncol Lett 2016 Dec 21;12(6):5075-5079. Epub 2016 Oct 21.

Department of Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.

Wilms tumor (WT) is the most common cancer that primarily develops in abdominal solid organ of children. It has no incipient symptom, and the most frequent symptoms are a painless, palpable abdominal mass. Proteomics technology was used to select the differentially expressed proteins of bilateral Wilms tumor (BWT). Ten serum samples of children with BWT were chosen, 20 serum samples of children with unilateral WT (UWT) and 20 serum samples of healthy children were selected, and proteomics technology was used to detect and collect data. Using bioinformatics, the data were analyzed and 10 difference peaks were obtained (P<0.01). Non-linear support vector machine was used to classify and to select the composite pattern with the highest Youdens index, and one differentially expressed protein with m/z of 5,648 kDa was obtained. A significantly high expression in children with BWT was obtained, and the expression intensity was also significantly (3,889.36±1,796.83) higher for children with BWT compared to those with UWT (2,886.81±1,404.65) and healthy children (432.21±730.42). Matrix-assisted laser desorption ionization/time-of-flight ionization/time-of-flight mass spectrometry was used for identification of the peak, and the peak was further identified as apolipoprotein C-III (APO C-III) by western blot analysis. In conclusion, to the best of our knowledge, a differentially expressed protein of APO C-III of BWT was obtained through proteomics technology for the first time, and it is expected to be a new marker for the early diagnosis and prognosis of BWT.
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http://dx.doi.org/10.3892/ol.2016.5306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228166PMC
December 2016

Exploration of Serum Proteomic Profiling and Diagnostic Model That Differentiate Crohn's Disease and Intestinal Tuberculosis.

PLoS One 2016 20;11(12):e0167109. Epub 2016 Dec 20.

Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.

Aim: To explore the diagnostic models of Crohn's disease (CD), Intestinal tuberculosis (ITB) and the differential diagnostic model between CD and ITB by analyzing serum proteome profiles.

Methods: Serum proteome profiles from 30 CD patients, 21 ITB patients and 30 healthy controls (HCs) were analyzed by using weak cationic magnetic beads combined with MALDI-TOF-MS technique to detect the differentially expressed proteins of serum samples. Three groups were made and compared accordingly: group of CD patients and HCs, group of ITB patients and HCs, group of CD patients and ITB patients. Wilcoxon rank sum test was used to screen the ten most differentiated protein peaks (P < 0.05). Genetic algorithm combining with support vector machine (SVM) was utilized to establish the optimal diagnostic models for CD, ITB and the optimal differential diagnostic model between CD and ITB. The predictive effects of these models were evaluated by Leave one out (LOO) cross validation method.

Results: There were 236 protein peaks differently expressed between group of CD patients and HCs, 305 protein peaks differently expressed between group of ITB patients and HCs, 332 protein peaks differently expressed between group of CD patients and ITB patients. Ten most differentially expressed peaks were screened out between three groups respectively (P < 0.05) to establish diagnostic models and differential diagnostic model. A diagnostic model comprising of four protein peaks (M/Z 4964, 3029, 2833, 2900) can well distinguish CD patients and HCs, with a specificity and sensitivity of 96.7% and 96.7% respectively. A diagnostic model comprising four protein peaks (M/Z 3030, 2105, 2545, 4210) can well distinguish ITB patients and HCs, with a specificity and sensitivity of 93.3% and 95.2% respectively. A differential diagnostic model comprising three potential biomarkers protein peaks (M/Z 4267, 4223, 1541) can well distinguish CD patients and ITB patients, with a specificity and sensitivity of 76.2% and 80.0% respectively. Among the eleven protein peaks from the diagnostic models and differential diagnostic model, two have been successfully purified and identified, Those two peaks were M/Z 2900 from the diagnostic model between CD and HCs and M/Z 1541 from the differential diagnostic model between CD and ITB. M/Z 2900 was identified as appetite peptide, M/Z 1541 was identified as Lysyl oxidase-like 2 (LOXL-2).

Conclusion: The differently expressed protein peaks analyzed by serum proteome with weak cationic magnetic beads combined MALDI-TOF-MS technique can effectively distinguish CD patients and HCs, ITB patients and HCs, CD patients and ITB patients. The diagnostic model between CD patients and HCs consisting of four protein peaks (M/Z 4964, 3029, 2833, 2900), the diagnostic model between ITB patients and HCs comprising four protein peaks (M/Z 3030, 2105, 2545, 4210) and the differential diagnostic model between CD patients and ITB patients comprising three protein peaks (M/Z 4267, 4223, 1541) had high specificity and sensitivity and can contribute to diagnoses of CD, ITB and the differential diagnosis between CD and ITB. Two proteins from the diagnostic model of CD and the differential diagnostic model between CD and ITB were identified. Further experiments are required using a larger cohort of samples.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167109PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173341PMC
June 2017

Proteins associated with EGFR-TKIs resistance in patients with non-small cell lung cancer revealed by mass spectrometry.

Mol Med Rep 2016 Nov 11;14(5):4823-4829. Epub 2016 Oct 11.

Department of Medical Oncology, Nanjing Medical University, Affiliated Hangzhou Hospital, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China.

The present study aimed to identify potential serum biomarkers for predicting the clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‑TKIs). A total of 61 samples were collected and analyzed using the integrated approach of magnetic bead‑based weak cation exchange chromatography and matrix‑assisted laser desorption/ionization‑time of flight‑mass spectrometry. The Zhejiang University Protein Chip Data Analysis system was used to identify the protein spectra of patients that are resistant and sensitive to EGFR‑TKIs. Furthermore, a support vector machine was used to construct a predictive model with high accuracy. The model was trained using 46 samples and tested with the remaining 15 samples. In addition, the ExPASy Bioinformatics Resource Portal was used to search potential candidate proteins for peaks in the predictive model. Seven mass/charge (m/z) peaks at 3,264, 9,156, 9,172, 3,964, 9,451, 4,295 and 3,983 Da, were identified as significantly different peaks between the EGFR‑TKIs sensitive and resistant groups. A predictive model was generated with three protein peaks at 3,264, 9,451 and 4,295 Da (m/z). This three‑peak model was capable of distinguishing EGFR‑TKIs resistant patients from sensitive patients with a specificity of 80% and a sensitivity of 80.77%. Furthermore, in a blind test, this model exhibited a high specificity (80%) and a high sensitivity (90%). Apelin, TYRO protein tyrosine kinase‑binding protein and big endothelin‑1 may be potential candidates for the proteins identified with an m/z of 3,264, 9,451 and 4,295 Da, respectively. The predictive model used in the present study may provide an improved understanding of the pathogenesis of NSCLC, and may provide insights for the development of TKI treatment plans tailored to specific patients.
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http://dx.doi.org/10.3892/mmr.2016.5823DOI Listing
November 2016

Regulation of DNA replication and chromosomal polyploidy by the MLL-WDR5-RBBP5 methyltransferases.

Biol Open 2016 Oct 15;5(10):1449-1460. Epub 2016 Oct 15.

Basic Science Division, Nevada Cancer Institute, Las Vegas, NV 89135, USA Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89154, USA

DNA replication licensing occurs on chromatin, but how the chromatin template is regulated for replication remains mostly unclear. Here, we have analyzed the requirement of histone methyltransferases for a specific type of replication: the DNA re-replication induced by the downregulation of either Geminin, an inhibitor of replication licensing protein CDT1, or the CRL4CDT2 ubiquitin E3 ligase. We found that siRNA-mediated reduction of essential components of the MLL-WDR5-RBBP5 methyltransferase complexes including WDR5 or RBBP5, which transfer methyl groups to histone H3 at K4 (H3K4), suppressed DNA re-replication and chromosomal polyploidy. Reduction of WDR5/RBBP5 also prevented the activation of H2AX checkpoint caused by re-replication, but not by ultraviolet or X-ray irradiation; and the components of MLL complexes co-localized with the origin recognition complex (ORC) and MCM2-7 replicative helicase complexes at replication origins to control the levels of methylated H3K4. Downregulation of WDR5 or RBBP5 reduced the methylated H3K4 and suppressed the recruitment of MCM2-7 complexes onto replication origins. Our studies indicate that the MLL complexes and H3K4 methylation are required for DNA replication but not for DNA damage repair.
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http://dx.doi.org/10.1242/bio.019729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087680PMC
October 2016

High-throughput proteomics integrated with gene microarray for discovery of colorectal cancer potential biomarkers.

Oncotarget 2016 Nov;7(46):75279-75292

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, China.

Proteins, as executives of genes' instructions, are responsible for cellular phenotypes. Integratingproteomics with gene microarray, we conducted this study to identify potential protein biomarkers of colorectal cancer (CRC). Isobaric tags with related and absolute quantitation (iTRAQ) labeling mass spectrometry (MS) was applied to screen and identify differentially expressed proteins between paired CRC and adjacent normal mucosa. Meanwhile, Affymetrix U133plus2.0 microarrays were used to perform gene microarray analysis. Verification experiments included immunohistochemistry (IHC), western blot and enzyme-linked immunosorbent assay (ELISA) of selected proteins. Overall, 5469 differentially expressed proteins were detected with iTRAQ-MS from 24 matched CRC and adjacent normal tissues. And gene microarray identified 39859 differential genes from 52 patients. Of these, 3083 differential proteins had corresponding differentially expressed genes, with 245 proteins and their genes showed >1.5-fold change in expression level. Gene ontology enrichment analysis revealed that up-regulated proteins were more involved in cell adhesion and motion than down-regulated proteins. In addition, up-regulated proteins were more likely to be located in nucleus and vesicles. Further verification experiments with IHC confirmed differential expression levels of 5 proteins (S100 calcium-binding protein A9, annexin A3, nicotinamide phosphoribosyltransferase, carboxylesterase 2 and calcium activated chloride channel A1) between CRC and normal tissues. Besides, western blot showed a stepwise increase of annexin A3 abundance in normal colorectal mucosa, adenoma and CRC tissues. ELISAresults revealed significantly higher serum levels of S100 calcium-binding protein A9 and annexin A3 in CRC patients than healthy controls, validating diagnostic value of these proteins. Cell experiments showed that inhibition of annexin A3 could suppress CRC cell proliferation and aggressiveness. S100 calcium-binding protein A9, annexin A3, nicotinamide phosphoribosyltransferase, carboxylesterase 2 and calcium activated chloride channel A1 were probably potential biomarkers of colorectal cancer. Annexin A3 was a potentially valuable therapeutic target of CRC.
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http://dx.doi.org/10.18632/oncotarget.12143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342740PMC
November 2016

Association between Oxidative DNA Damage and Risk of Colorectal Cancer: Sensitive Determination of Urinary 8-Hydroxy-2'-deoxyguanosine by UPLC-MS/MS Analysis.

Sci Rep 2016 09 2;6:32581. Epub 2016 Sep 2.

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.

Oxidative DNA damage plays crucial roles in the pathogenesis of numerous diseases including cancer. 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the most representative product of oxidative modifications of DNA, and urinary 8-OHdG is potentially the best non-invasive biomarker of oxidative damage to DNA. Herein, we developed a sensitive, specific and accurate method for quantification of 8-OHdG in human urine. The urine samples were pretreated using off-line solid-phase extraction (SPE), followed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. By the use of acetic acid as an additive to the mobile phase, we improved the UPLC-MS/MS detection of 8-OHdG by 2.7-5.3 times. Using the developed strategy, we measured the contents of 8-OHdG in urine samples from 142 healthy volunteers and 84 patients with colorectal cancer (CRC). We observed increased levels of urinary 8-OHdG in patients with CRC and patients with tumor metastasis, compared to healthy controls and patients without tumor metastasis, respectively. Additionally, logistic regression analysis and receiver operator characteristic (ROC) curve analysis were performed. Our findings implicate that oxidative stress plays important roles in the development of CRC and the marked increase of urinary 8-OHdG may serve as a potential liquid biomarker for the risk estimation, early warning and detection of CRC.
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http://dx.doi.org/10.1038/srep32581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009303PMC
September 2016

Common housekeeping proteins are upregulated in colorectal adenocarcinoma and hepatocellular carcinoma, making the total protein a better "housekeeper".

Oncotarget 2016 Oct;7(41):66679-66688

Bio-X Institutes, Key Laboratory for The Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200030, PR China.

Housekeeping proteins are essential endogenous controls for normalization as they are expected to be stably expressed. However, the stability of the expression level of housekeeping proteins needs to be assessed considering various experimental conditions. Our study evaluated the degree of variability of 7 commonly used housekeeping proteins with regard to their potential utility as normalizers in 56 pairs of matched colorectal adenocarcinoma (CRC) tissue samples and 6 pairs of hepatocellular carcinoma (HCC) tissue samples using multiple reaction monitoring (MRM) and Western blot analyses. A comprehensive experimental design and strict statistical analysis revealed that the expression levels of these 7 housekeeping proteins were not as stable as expected and they all exhibited upregulations to varying degrees in both the CRC and the HCC tissue samples. Consequently, we verified that using the amount of total protein instead of that of an individual protein can serve as a preferable control for studies of protein expression that require normalization.
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http://dx.doi.org/10.18632/oncotarget.11439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341829PMC
October 2016

[New progression of translational research on colorectal cancer].

Zhonghua Wei Chang Wai Ke Za Zhi 2016 Jun;19(6):601-6

Cancer Institute of Zhejiang University, Key Laboratory of Cancer Prevention and Intervention (China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.

Precision medicine is becoming the goal of translational research on colorectal cancer. Accurate molecular subtyping contributes to better guidance of clinical practice. The current TNM staging system of colorectal cancer is inadequate in terms of guiding clinical practice, such as the underestimation of prognosis of with stage II( and III( colorectal cancer TNM staging, and identification of high-risk and low-risk patients with stage II( colorectal cancer. Researchers from Europe and US have proposed a number of molecular subtypings with clinicopathological phenotypes and molecular phenotypes, which has certain practical significance and is beneficial to the choice of treatment regimen and targeted drugs. But the current results of subtyping research require further validations by clinical large scale multi-center trials. Based on precision medicine, molecular subtyping gradually reveals its clinical significance and is optimized through combining genomics with various clinical phenotypes, indicating its guidance for clinical practice, which is the inevitable course of precision medicine accomplishment. In recent years, there have been many new advances in colorectal cancer liver metastasis treatment. The prognosis of colorectal cancer patients undergoing resection of liver metastasis lesion is similar to those with stage III(. Early recurrence within 6 months after translational treatment and resection occurred in about one third of the patients with initially unresectable liver metastasis, and the overall survival was poor. Thus, an evaluation system should be established in order to avoid the strong therapy and strive for better quality of life in some patients. Individualized treatment for colorectal cancer is emphasized increasingly. Body fluid (peripheral blood and urine) marker detection is a recent research hotspot, including serum protein(polypeptide), plasma miRNA, circulating tumor cells and circulating nucleic acid.
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June 2016

Diagnostic and prognostic significance of serum apolipoprotein C-I in triple-negative breast cancer based on mass spectrometry.

Cancer Biol Ther 2016 06 3;17(6):635-47. Epub 2016 Jun 3.

a Department of Pediatric Surgery , First Affiliated Hospital, Zhengzhou University , Zhengzhou , PR China.

Women with triple-negative breast cancer (TNBC) have poor prognosis because of the aggressive nature of the tumor, delayed diagnosis and non-specific symptoms in the early stages. Identification of novel specific TNBC serum biomarkers for screening and therapeutic purposes therefore remains an urgent clinical requirement.We obtained serum samples from a total of 380 recruited individuals split into mining and testing sets, with the aim of screening for reliable protein biomarkers from TNBC and non-TNBC (NTNBC) sera. Samples were assessed using mass spectrometry, followed by receiver operating characteristic (ROC), survival and hazard function curve as well as multivariate Cox regression analyses to ascertain the potential of the protein constituents as diagnostic and prognostic biomarkers for TNBC.We identified upregulated apolipoprotein C-I (apoC-I) with a validated positive effect on TNBC tumorigenesis, with confirmation in an independent test set and minimization of systematic bias by pre-analytical parameters. The apoC-I protein had superior diagnostic ability in distinguishing between TNBC and NTNBC cases. Moreover, the protein presented a more robust potential prognostic factor for TNBC than NTNBC. The apoC-I protein identified in this study presents an effective novel diagnostic and prognostic biomarker for TNBC, indicating that measurement of the peak intensity at 7785 Da in serum samples could facilitate improved early detection and estimation of postoperative survival prognosis for TNBC.
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http://dx.doi.org/10.1080/15384047.2016.1156262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990397PMC
June 2016

Diagnostic and prognostic role of serum protein peak at 6449 m/z in gastric adenocarcinoma based on mass spectrometry.

Br J Cancer 2016 Apr 22;114(8):929-38. Epub 2016 Mar 22.

Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

Background: Gastric cancer (GC) is a highly aggressive cancer type associated with significant mortality owing to delayed diagnosis and non-specific symptoms observed in the early stages. Therefore, identification of novel specific GC serum biomarkers for screening purposes is an urgent clinical requirement.

Methods: This study recruited a total of 432 serum samples from 296 GC patients split into the mining and testing sets. We aimed to screen for reliable protein biomarkers from matched serum samples based on mass spectrometry, followed by comparison with three representative conventional markers using receiver operating characteristic and survival curve analyses to ascertain their potential values as diagnostic and prognostic biomarkers for GC.

Results: We identified an apoC-III fragment with confirmation in an independent test set from a second hospital. We found that the diagnostic ability of this fragment performed better than current standard GC diagnostic biomarkers both individually and in combination in distinguishing patients with GC from healthy individuals. Moreover, we found that this apoC-III protein fragment represents a more robust potential prognostic factor for GC than the three conventional markers.

Conclusions: In view of these findings, we suggest that apoC-III protein fragment is a novel diagnostic and prognostic biomarker, a complement to conventional biomarkers in detecting GC.
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http://dx.doi.org/10.1038/bjc.2016.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984799PMC
April 2016

Screening and identification of post-traumatic stress-related serum factors in children with Wilms' tumors.

Oncol Lett 2016 Feb 11;11(2):1299-1304. Epub 2016 Jan 11.

Department of Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.

Wilms' tumors are one of the most common malignant, solid intra-abdominal tumors observed in children. Although potential tumor markers have been found, inflammatory cytokines interfere with the process of specific protein identification. The present study was undertaken to identify post-traumatic stress-related factors of Wilms' tumors and to verify the accuracy of early-stage tumor-specific serum protein markers. Serum samples were screened for differentially-expressed proteins using surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS). Potential markers were isolated and purified using solid-phase extraction (SPE) and SDS-PAGE. Following enzymatic digestion of the protein samples, the peptide fragments were detected with high performance liquid chromatography-mass spectrometry. The obtained peptide mass fingerprint was searched in the Swiss-Prot protein sequence database via the Mascot search engine. Differentially-expressed proteins were verified using western blot analysis. Differentially-expressed proteins with a mass/charge of 5,816 were screened out using SELDI-TOF-MS, and significant differences between the tumor and control groups, and the trauma and control groups were observed. Target proteins were isolated and purified using SPE and SDS-PAGE. Thioredoxin 1 (Trx1) was found to be differentially expressed. In the serum of children with Wilms' tumors, there was an increase in the level of the post-traumatic stress-related inflammatory factor, Trx1, as compared with the normal control group. Thus, the results of this study indicate that Trx1 presents a potential post-traumatic stress-related factor of Wilms' tumors.
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http://dx.doi.org/10.3892/ol.2016.4099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734303PMC
February 2016