Publications by authors named "Wangxiong Hu"

30 Publications

  • Page 1 of 1

Characterization and discrimination of human colorectal cancer cells using terahertz spectroscopy.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Jul 17;256:119713. Epub 2021 Mar 17.

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

Terahertz technology has been widely used in biomedical research. Herein, terahertz time-domain attenuated total reflection (THz TD-ATR) spectroscopy was employed to characterize and discriminate human cancer cell lines (DLD-1 and HT-29). Terahertz responses of the cell lines were measured and Savitzky-Golay algorithm was applied to smooth the spectra of refractive index, absorption coefficient and dielectric loss tangent in terahertz regime. Principal component analysis (PCA) was then adopted for feature extraction and cell characterization. Based on the processed data, cancer cell lines were discriminated by applying random forests (RF) method to analyze three characteristic parameters separately and the results from them were compared. Results indicate that absorption coefficient was the most sensitive parameter for cancer cell discrimination. Our study suggests great potential for human cancer cell recognition and provides experimental basis for liquid biopsy.
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http://dx.doi.org/10.1016/j.saa.2021.119713DOI Listing
July 2021

HomeoboxC6 promotes metastasis by orchestrating the DKK1/Wnt/β-catenin axis in right-sided colon cancer.

Cell Death Dis 2021 04 1;12(4):337. Epub 2021 Apr 1.

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

Patients with right-sided colon cancer (RCC) generally have a poorer prognosis than those with left-sided colon cancer (LCC). We previously found that homeobox C6 (HOXC6) was the most significantly upregulated gene in RCC compared to LCC. However, it remains unclear whether HOXC6 plays a role in tumor proliferation and metastasis. Our study aimed to explore the potential oncogenic role and the detailed molecular mechanism of HOXC6 in RCC. In this study, HOXC6 was validated to be overexpressed in RCC and associated with poor prognosis. Furthermore, overexpression of HOXC6 promoted the migration and invasion of colon cancer cells through inducing EMT by activating the Wnt/β-catenin signaling pathway and inhibition of DKK1 secretion. Lastly, we preliminary explored the translational effect of HOXC6 and found that silencing of HOXC6 made HCT116 and HT29 cells more sensitive to irinotecan.
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http://dx.doi.org/10.1038/s41419-021-03630-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016886PMC
April 2021

Hypermutated tumours across 11 cancer types show three distinct immune subtypes.

Eur J Cancer 2021 May 19;148:230-238. Epub 2021 Mar 19.

Key Laboratory of Reproductive and Genetics, Ministry of Education, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China. Electronic address:

Background: Complete remission is observed in less than half of hypermutated (HM) tumours after immune checkpoint blockade therapy, indicating that HM tumours are very heterogeneous. Thus, there is an urgent requirement to decipher the unknown intrinsic HM tumour subtypes.

Methods: Statistical analysis was performed on somatic mutation data from 5519 tumours across 11 cancer types obtained from The Cancer Genome Atlas and 338 colorectal cancer (CRC) samples obtained from an Asian cohort. Samples with a tumour mutation burden >10 mut/Mb were classified as HM. A total of 1040 HM samples harbouring corresponding transcriptomes were used for non-negative matrix factorisation clustering. Tumour mutational burden, neoantigens, T cell receptor (TCR) diversity, stromal score and immune score were compared between the subtypes.

Results: HM tumours fell into three distinct immune subtypes: HM1, HM2 and HM3. HM3 tumours were correlated with increased CD8 T cell infiltration, high TCR diversity, a high immune score and prolonged survival. HM2 tumours were correlated with an abundant stromal component, epithelial-mesenchymal transition, TGFβ, angiogenesis hallmarks and poor outcomes. The infiltration of more CD8 T cells and increased chemokine expression in HM3 were validated in CRC by immunofluorescence.

Conclusions: These findings will facilitate the development of a subtype-oriented therapy strategy to enhance the treatment effect in the near future.
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http://dx.doi.org/10.1016/j.ejca.2021.01.044DOI Listing
May 2021

Pan-cancer analyses demonstrate that ANKRD6 is associated with a poor prognosis and correlates with M2 macrophage infiltration in colon cancer.

Chin J Cancer Res 2021 Feb;33(1):93-102

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

Objective: Ankyrin repeat domain-containing protein 6 (ANKRD6) is an ankyrin repeat-containing protein which is structurally related to vertebrate inversin and Drosophila Diego. However, the correlations between ANKRD6 and tumor-infiltrating immune cells in cancers is not clear.

Methods: ANKRD6 expression was analyzed by Oncomine, Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). PrognoScan and GEPIA were used to evaluate the influence of ANKRD6 on clinical prognosis. TIMER and CIBERSORT were used to analyze correlations between ANKRD6 expression levels and tumor immune cell infiltrates. Immunohistochemical analysis of the relationship between ANKRD6 expression and overall survival, as well as the relationship between ANKRD6 expression and M2 macrophage infiltration, was performed.

Results: High level of ANKRD6 expression was associated with poor prognosis of colon cancer. ANKRD6 expression level was positively correlated with infiltrating levels of CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells in colon cancer by using TIMER. Using CIBERSORT, we found that in plasma cells, CD8+ T cells, CD4+ memory resting T cells, follicular helper T cells and activated natural killer cells were significantly lower in the ANKRD6-high group than in the ANKRD6-low group. M0 and M2 macrophages were significantly higher in the ANKRD6-high group than in the ANKRD6-low group. Immunohistochemistry confirmed that M2 macrophage infiltration in the ANKRD6-high group significantly increased.

Conclusions: The high ANKRD6 expression is associated with poor prognosis of colon cancer. ANKRD6 expression is positively correlated with M2 macrophage infiltration in colon cancer.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2021.01.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941690PMC
February 2021

Survival outcome and prognostic factors for colorectal cancer with synchronous bone metastasis: a population-based study.

Clin Exp Metastasis 2021 02 9;38(1):89-95. Epub 2021 Jan 9.

Department of Abdominal Oncology, West China Hospital of Medicine, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, People's Republic of China.

Prognostic factors of synchronous bone metastatic colorectal cancer (CRC) are still undetermined. We aimed to investigate survival outcome and prognostic factors of patients with synchronous bone metastatic CRC. Information of patients with synchronous bone metastatic CRC were obtained from the Surveillance, Epidemiology, and End Results (SEER) and West China Hospital (WCH) databases. Cases from SEER database composed construction cohort, while cases from WCH database were used as validation cohort. A novel nomogram was constructed to predict individual survival probability based on Cox regression model. The performance of the nomogram was internally and externally validated using calibration curves and concordance index (C-index). Three hundred and eighty-one patients from SEER database were eligible. The median disease specific OS was 9.0 months (95% confidence interval [CI]: 7.3-10.7 months). Multivariate Cox analysis identified seven independent prognostic factors including histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis. A novel nomogram was established based on these variables. In the internal validation, the C-index (0.72, 95% CI 0.69-0.75) and calibration curve indicated well performance of this nomogram at predicting survival outcome in bone metastatic CRC. In the external validation, the C-index was 0.57 (95% CI 0.46-0.68). The prognosis of synchronous bone metastatic CRC is very poor. Histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis are independent prognostic factors. Further study is warranted to confirm the practicality of the prognostic nomogram.
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http://dx.doi.org/10.1007/s10585-020-10069-5DOI Listing
February 2021

Hypoxia Correlates With Poor Survival and M2 Macrophage Infiltration in Colorectal Cancer.

Front Oncol 2020 20;10:566430. Epub 2020 Nov 20.

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

Background: It is widely accepted that the oxygen level in tumor tissue is significantly lower than the adjacent normal tissue, thus termed hypoxia. Intratumoral hypoxia represents a major driving force in cancer progression, recurrence, metastasis, and decreased survival. Though multiple gene signatures reflect the complex cellular response to hypoxia have been established in several cancer types such as head and neck, breast, and lung cancers, the hypoxic panorama in colorectal cancer (CRC) remains poorly understood.

Methods: A hypoxic signature constituted by a total of 356 genes, including canonical hypoxia-responsive ADM, ANGPTL4, CA9, and VEGFA, was established based on systemic literature search. A total of 1,730 CRC samples across four independent cohorts were used for Prognosis, molecular signatures, pathways, and tumor-infiltrating lymphocytes were compared between the subtypes.

Results: CRCs mainly fell into two subgroups, one indicated as hypoxia and the other one designated as normoxia. Hypoxia was correlated with poor outcomes in CRC and will increase the risk of a subset of stage II patients to the level of normoxic stage III. Additionally, hypoxia was closely associated with activation of RAS signaling pathway independent of mutation. More M2 macrophage infiltration was another hypoxic marker indicated that subsets of patients with high M2 macrophages may benefit from macrophage-targeting therapy.

Conclusions: These findings will facilitate the development of a hypoxia-oriented therapy strategy to enhance the treatment effect in the near future.
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http://dx.doi.org/10.3389/fonc.2020.566430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714992PMC
November 2020

Ultra-mutated colorectal cancer patients with POLE driver mutations exhibit distinct clinical patterns.

Cancer Med 2021 01 30;10(1):135-142. Epub 2020 Oct 30.

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

POLE mutations, which lead to an ultramutated phenotype in colorectal cancer (CRC), have been reported as a promising marker in immunotherapy. We performed sequencing of CRC cases in Zhejiang University (ZJU) and extracted obtainable data from recently published results, including The Cancer Genome Atlas (TCGA), Japanese studies and clinical trials, to present clinical patterns of POLE driver-mutated CRC and reveal its heterogeneity. The rate of somatic POLE driver mutations has been reported as 2.60% (ZJU cohort), 1.50% (TCGA cohort), 1.00% (Japan cohort), and 1.00% (Lancet cohort). POLE driver mutations show a clearly increased mutation burden (mean TMB: 217.98 mut/Mb in ZJU; 203.13 mut/Mb in TCGA). Based on pooled data, more than 70.00% of patients with POLE driver mutations were diagnosed before they were 55 years old and at an early disease stage (Stage 0-II >70.00%), and more than 70.00% were male. Among Asian patients, 68.40% developed POLE driver mutations in the left-side colon, whereas 64.00% of non-Asian patients developed them in the right-side colon (p < 0.01). The top three amino acid changes due to POLE driver mutations are P286R, V411L, and S459F. Investigators and physicians should ascertain the heterogeneity and clinical patterns of POLE driver mutations to be better equipped to design clinical trials and analyze the data.
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http://dx.doi.org/10.1002/cam4.3579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826451PMC
January 2021

Hypermethylation of Promoter Is a Biomarker Across 12 Cancer Types.

DNA Cell Biol 2020 Nov 9;39(11):2052-2058. Epub 2020 Sep 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, China.

Aberrant DNA methylation is thought to be an early event in cancer development. Thus, identification of DNA methylation-based markers may provide valuable evidence in clinical decision-making. In this study, a DNA methylation dataset from 514 normal-tumor pairs is used to explore possible shared differentially methylated regions (DMRs) across 12 cancer types. Results showed that DMR in Dopamine receptor D5 () promoter may be serviced as a good candidate biomarker across different cancer types. We further validated the extended DMR (292bp) in promoter using SEQUENOM MassARRAY platform. Detection of promoter dynamic methylation will allow rapid risk assessment at diagnosis, for suspicious tumor with the tissue biopsies.
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http://dx.doi.org/10.1089/dna.2020.5829DOI Listing
November 2020

Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival.

J Med Genet 2021 01 13;58(1):12-19. Epub 2020 Mar 13.

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

Background: Microsatellite instability-high (MSI-H) tumour patients generally have a better prognosis than microsatellite-stable (MSS) ones due to the large number of non-synonymous mutations. However, an increasing number of studies have revealed that less than half of MSI-H patients gain survival benefits or symptom alleviation from immune checkpoint-blockade treatment. Thus, an in-depth inspection of heterogeneous MSI-H tumours is urgently required.

Methods: Here, we used non-negative matrix factorisation (non-NMF)-based consensus clustering to define stomach adenocarcinoma (STAD) MSI-H subtypes in samples from The Cancer Genome Atlas and an Asian cohort, GSE62254.

Results: MSI-H STAD samples are basically clustered into two subgroups (MSI-H1 and MSI-H2). Further examination of the immune landscape showed that immune suppression factors were enriched in the MSI-H1 subgroup, which may be associated with the poor prognosis in this subgroup.

Conclusions: Our results illustrate the genetic heterogeneity within MSI-H STADs, with important implications for cancer patient risk stratification, prognosis and treatment.
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http://dx.doi.org/10.1136/jmedgenet-2019-106609DOI Listing
January 2021

Significant prognostic values of differentially expressed-aberrantly methylated hub genes in breast cancer.

J Cancer 2019 21;10(26):6618-6634. Epub 2019 Oct 21.

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.

: Abnormal status of gene expression plays an important role in tumorigenesis, progression and metastasis of breast cancer. Mechanisms of gene silence or activation were varied. Methylation of genes may contribute to alteration of gene expression. This study aimed to identify differentially expressed hub genes which may be regulated by DNA methylation and evaluate their prognostic value in breast cancer by bioinformatic analysis. : GEO2R was used to obtain expression microarray data from GSE54002, GSE65194 and methylation microarray data from GSE20713, GSE32393. Differentially expressed-aberrantly methylated genes were identified by FunRich. Biological function and pathway enrichment analysis were conducted by DAVID. PPI network was constructed by STRING and hub genes was sorted by Cytoscape. Expression and DNA methylation of hub genes was validated by UALCAN and MethHC. Clinical outcome analysis of hub genes was performed by Kaplan Meier-plotter database for breast cancer. IHC was performed to analyze protein levels of EXO1 and Kaplan-Meier was used for survival analysis. : 677 upregulated-hypomethylated and 361 downregulated-hypermethylated genes were obtained from GSE54002, GSE65194, GSE20713 and GSE32393 by GEO2R and FunRich. The most significant biological process, cellular component, molecular function enriched and pathway for upregulated-hypomethylated genes were viral process, cytoplasm, protein binding and cell cycle respectively. For downregulated-hypermethylated genes, the result was peptidyl-tyrosine phosphorylation, plasma membrane, transmembrane receptor protein tyrosine kinase activity and Rap1 signaling pathway (All p< 0.05). 12 hub genes (TOP2A, MAD2L1, FEN1, EPRS, EXO1, MCM4, PTTG1, RRM2, PSMD14, CDKN3, H2AFZ, CCNE2) were sorted from 677 upregulated-hypomethylated genes. 4 hub genes (EGFR, FGF2, BCL2, PIK3R1) were sorted from 361 downregulated-hypermethylated genes. Differential expression of 16 hub genes was validated in UALCAN database (p<0.05). 7 in 12 upregulated-hypomethylated and 2 in 4 downregulated-hypermethylated hub genes were confirmed to be significantly hypomethylated or hypermethylated in breast cancer using MethHC database (p<0.05). Finally, 12 upregulated hub genes (TOP2A, MAD2L1, FEN1, EPRS, EXO1, MCM4, PTTG1, RRM2, PSMD14, CDKN3, H2AFZ, CCNE2) and 3 downregulated genes (FGF2, BCL2, PIK3R1) contributed to significant unfavorable clinical outcome in breast cancer (p<0.05). High expression level of EXO1 protein was significantly associated with poor OS in breast cancer patients (p=0.03). : Overexpression of TOP2A, MAD2L1, FEN1, EPRS, EXO1, MCM4, PTTG1, RRM2, PSMD14, CDKN3, H2AFZ, CCNE2 and downregulation of FGF2, BCL2, PIK3R1 might serve as diagnosis and poor prognosis biomarkers in breast cancer by more research validation. EXO1 was identified as an individual unfavorable prognostic factor. Methylation might be one of the major causes leading to abnormal expression of those genes. Functional analysis and pathway enrichment analysis of those genes would provide novel ideas for breast cancer research.
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http://dx.doi.org/10.7150/jca.33433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856906PMC
October 2019

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

Subtyping of microsatellite instability-high colorectal cancer.

Cell Commun Signal 2019 07 22;17(1):79. Epub 2019 Jul 22.

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

Background: Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) generally have a better prognosis than patients with microsatellite stable (MSS) CRC. However, some MSI-H CRC patients do not gain overall survival benefits from immune checkpoint-blockade treatment. In other words, heterogeneity within the subgroup of MSI-H tumors remains poorly understood. Thus, an in-depth molecular characterization of MSI-H tumors is urgently required.

Methods: Here, we use nonnegative matrix factorization (NMF)-based consensus clustering to define CRC MSI-H subtypes in The Cancer Genome Atlas and a French multicenter cohort GSE39582. CIBERSORT was used to calculate the proportions of 22 lymphocytes in tumor tissue in MSI-H subtypes.

Results: MSI-H CRC samples basically clustered into two subgroups (MSI-H1 and MSI-H2). MSI-H1 was characterized by a lower BRAF mutational status, higher frequency of chromosomal instability, global hypomethylation, and worse survival than MSI-H2. Further examination of the immune landscape showed that macrophages of the M2 phenotype were enriched in MSI-H1, which may be associated with poor prognosis in this subgroup.

Conclusions: Our results illustrate the genetic heterogeneity in MSI-H CRCs and macrophages may serve as good targets for anticancer therapy in MSI-H1.
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http://dx.doi.org/10.1186/s12964-019-0397-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647262PMC
July 2019

PTPRB promotes metastasis of colorectal carcinoma via inducing epithelial-mesenchymal transition.

Cell Death Dis 2019 04 30;10(5):352. Epub 2019 Apr 30.

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.

Dysregulation of protein tyrosine phosphatase, receptor type B (PTPRB) correlates with the development of a variety of tumors. Here we show that PTPRB promotes metastasis of colorectal cancer (CRC) cells via inducing epithelial-mesenchymal transition (EMT). We find that PTPRB is expressed at significantly higher levels in CRC tissues compared to adjacent nontumor tissues and in CRC cell lines with high invasion. PTPRB knockdown decreased the number of invasive CRC cells in an in vitro wound healing model, and also reduced tumor metastasis in vivo. Conversely, PTPRB overexpression promoted CRC cell invasion in vitro and metastasis in vivo. PTPRB overexpression decreased vimentin expression and promoted E-cadherin expression, consistent with promotion of EMT, while PTPRB knockdown had the opposite effect. Hypoxic conditions induced EMT and promoted invasion in CRC cells, but these effects were eliminated by PTPRB knockdown. EMT blockade via TWIST1 knockdown inhibited the migration and invasiveness of CRC cells, and even increased PTPRB expression could not reverse this effect. Altogether, these data support the conclusion that PTPRB promotes invasion and metastasis of CRC cells via inducing EMT, and that PTPRB would be a novel therapeutic target for the treatment of CRC.
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http://dx.doi.org/10.1038/s41419-019-1554-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491493PMC
April 2019

A novel 4-gene prognostic signature for hypermutated colorectal cancer.

Cancer Manag Res 2019 4;11:1985-1996. Epub 2019 Mar 4.

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

Background: Hypermutated colorectal cancer (CRC) reportedly accounts for 15%-17% of all cases of CRC. However, the proportion and number of patients with hypermutated CRC cannot be unappreciated. Additionally, therapy options for these patients differ from those for CRC patients, with a greater potential benefit from immunotherapy.

Materials And Methods: We sequenced the tumor mucosa of CRC patients with >24 months of follow-up data at our center and identified mutation profiles of hypermutated CRC as a training data set (Zhejiang University [ZJU]); we then collected patients from The Cancer Genome Atlas (TCGA) as a validation data set. Recurrently mutated genes were combined to calculate a compound score via Cox proportional hazards model. Patients with higher-than-median scores were segregated as the high-risk group. Outcomes were analyzed by Kaplan-Meier and Cox regression analyses using Python (3.6.0) and R (3.4.0).

Results: We constructed a 4-gene signature (, and ), with training in 45 hypermutated patients at ZJU and validation in 24 hypermutated patients from TCGA. Patients in the high-risk group showed poor survival (adjusted HR =9.85, 95% CI: 2.07-46.81, =0.004). Further subgroup analysis was performed for stage II and III colon cancer (HR =10.91, 95% CI: 1.36-87.5, =0.005) and high microsatellite instability (MSI-H) CRC (HR =12.57, 95% CI: 1.57-100.69, =0.002) subgroups, which verified that our signature is universal. We then compared our prognostic signature with other risk factors (including MSI status, POLE driver mutation, BRAF-p.V600E, tumor mutational burden, and TNM staging). The results proved that our 4-gene signature is better than the other risk factor for prognosis in hypermutated CRC.

Conclusion: Our 4-gene signature is a good predictor of survival for hypermutated CRC, and this signature is powerful in stage II and III colon cancer and MSI-H CRC. Future prospective studies are needed to confirm the power of the 4-gene signature in patients receiving immunotherapy.
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http://dx.doi.org/10.2147/CMAR.S190963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407520PMC
March 2019

Deciphering molecular properties of hypermutated gastrointestinal cancer.

J Cell Mol Med 2019 01 31;23(1):370-379. Epub 2018 Oct 31.

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

Great mutational heterogeneity is observed both across cancer types (>1000-fold) and within a given cancer type, with a fraction harboring >10 mutations per million bases, thus termed hypermutation. We determined the genome-wide effects of high mutation load on the transcriptome and methylome of two cancer types; namely, colorectal cancer (CRC) and stomach adenocarcinoma (STAD). Briefly, hierarchical clustering of the expression and methylation profiles showed that the majority of CRC and STAD hypermutated samples were mixed and separated from their respective non-hypermutated samples, exceeding the boundary of tissue specificity. Further in-detailed exploration uncovered that the underlying molecular mechanism may be related to the perturbation of chromatin remodeling genes.
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http://dx.doi.org/10.1111/jcmm.13941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307802PMC
January 2019

Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis.

Carcinogenesis 2018 12;39(11):1368-1379

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, China.

Liver metastases develop in more than half of the patients with colorectal cancer (CRC) and are associated with a poor prognosis. The factors influencing liver metastasis of CRC are poorly characterized, but this information is urgently needed. We have now discovered that small extracellular vesicles (sEVs; exosomes) derived from CRC can be specifically targeted to liver tissue and induce liver macrophage polarization toward an interleukin-6 (IL-6)-secreting proinflammatory phenotype. More importantly, we found that microRNA-21-5p (miR-21) was highly enriched in CRC-derived sEVs and was essential for creating a liver proinflammatory phenotype and liver metastasis of CRC. Silencing either miR-21 in CRC-sEVs or Toll-like receptor 7 (TLR7) in macrophages, to which miR-21 binds, abolished CRC-sEVs' induction of proinflammatory macrophages. Furthermore, miR-21 expression in plasma-derived sEVs was positively correlated with liver metastasis in CRC patients. Collectively, our data demonstrate a pivotal role of CRC-sEVs in promoting liver metastasis by inducing an inflammatory premetastatic niche through the miR-21-TLR7-IL-6 axis. Thus, sEVs-miR-21 represents a potential prognostic marker and therapeutic target for CRC patients with liver metastasis.
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http://dx.doi.org/10.1093/carcin/bgy115DOI Listing
December 2018

Multi-omics Approach Reveals Distinct Differences in Left- and Right-Sided Colon Cancer.

Mol Cancer Res 2018 03 29;16(3):476-485. Epub 2017 Nov 29.

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.

Increasing evidence suggests that left-sided colon cancer (LCC) and right-sided colon cancer (RCC) are emerging as two different colorectal cancer types with distinct clinical characteristics. However, the discrepancy in the underlying molecular event between these types of cancer has not been thoroughly elucidated to date and warrants comprehensive investigation. To this end, an integrated dataset from The Cancer Genome Atlas was used to compare and contrast LCC and RCC, covering mutation, DNA methylation, gene expression, and miRNA. Briefly, the signaling pathway cross-talk is more prevalent in RCC than LCC, such as RCC-specific PI3K pathway, which often exhibits cross-talk with the RAS and P53 pathways. Meanwhile, methylation signatures revealed that RCC was hypermethylated relative to LCC. In addition, differentially expressed genes ( = 253) and differentially expressed miRNAs ( = 16) were determined between LCC and RCC. Especially for Prostate Cancer Susceptibility Candidate 1 (), a gene that was closely associated with hypermethylation, was the top significantly downregulated gene in RCC. Multi-omics comparison of LCC and RCC suggests that there are more aggressive markers in RCC and that tumor heterogeneity occurs within the location-based subtypes of colon cancer. These results clarify the debate regarding the conflicting prognosis between LCC and RCC, as proposed by different studies. The underlying molecular features present in LCC and RCC identified in this study are beneficial for adopting reasonable therapeutic approaches to prolong overall survival and progression-free survival in colorectal cancer patients. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0483DOI Listing
March 2018

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

ANGPTL1 attenuates colorectal cancer metastasis by up-regulating microRNA-138.

J Exp Clin Cancer Res 2017 06 12;36(1):78. Epub 2017 Jun 12.

Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, 310009, China.

Background: Angiopoietin-like protein 1 (ANGPTL1) has been reported to suppress migration and invasion in lung and breast cancer, acting as a novel tumor suppressor candidate. Nevertheless, its effects on colorectal cancer (CRC) remain poorly defined. In this study, we aim to demonstrate the biological function of ANGPTL1 in CRC cells.

Methods: We explored ANGPTL1 mRNA expression in human CRC tissues and its association with prognosis. CRC cell lines overexpressing ANGPTL1 or with ANGPTL1 knocked down were constructed and analyzed for changes in proliferation, colony formation, migration and invasion. ANGPTL1-regulated microRNAs were analyzed, and microRNA inhibitor and mimics were used to explore the role of microRNA in ANGPTL1-associated biological function.

Results: ANGPTL1 mRNA expression was down-regulated in CRC tissues, and high ANGPTL1 expression predicted better survival in CRC patients. ANGPTL1 overexpression resulted in suppressed migration and invasion in vitro, and it prolonged overall survival in mouse models. By contrast, its down-regulation enhanced migration and invasion of CRC cells. MicroRNA-138 expression was positively correlated with ANGPTL1 mRNA level in CRC tissues and up-regulated by ANGPTL1 in CRC cells. In addition, the microRNA-138 inhibitor or mimics could reverse or promote the ANGPTL1-mediated inhibition of the migratory capacity of CRC cells, respectively.

Conclusions: This study is the first to demonstrate the biological function of ANGPTL1 in CRC cells. ANGPTL1 expression was down-regulated in CRC tissues and inversely correlated with poor survival. ANGPTL1 repressed migration and invasion of CRC cells, and microRNA-138 was involved in this process.
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http://dx.doi.org/10.1186/s13046-017-0548-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467265PMC
June 2017

Pan-organ transcriptome variation across 21 cancer types.

Oncotarget 2017 Jan;8(4):6809-6818

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.

It is widely accepted that some messenger RNAs are evolutionarily conserved across species, both in sequence and tissue-expression specificity. To date, however, little effort has been made to exploit the transcriptome divergence between cancer and adjacent normal tissue at the pan-organ level. In this work, a transcriptome sequencing dataset from 675 normal-tumor pairs, representing 21 solid organs in The Cancer Genome Atlas, is used to evaluate expression evolution. The results show that in most cancer types, gene expression divergence and organ-specificity are reduced in cancer tissue compared to adjacent normal tissue. Furthermore, we observe that all cancers share cell cycle dysregulation through interrogating differentially expressed protein coding genes. Meanwhile, weighted correlation network analysis is used to detect of the gene module structure variation between cancer and adjacent normal tissue. And modules consisting of tightly co-regulated genes in cancer change substantially compared with those in adjacent normal tissue. We thus assume that the destruction of a coordinated regulatory network might result in tumorigenesis and tumor progression. Our results provide new insights into the complex cancer biology and shed light on the mysterious regulation mode for cancer.
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http://dx.doi.org/10.18632/oncotarget.14303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351671PMC
January 2017

Risk of eighteen genome-wide association study-identified genetic variants for colorectal cancer and colorectal adenoma in Han Chinese.

Oncotarget 2016 Nov;7(47):77651-77663

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), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: Recent genome-wide association studies (GWAS) identified eighteen single-nucleotide polymorphisms (SNPs) to be significantly associated with the risk of colorectal cancer (CRC). However, overall results of the following replications are inconsistent and little is known about whether these associations also exit in colorectal adenomas (CRA).

Methods: The SNP genotyping was performed using a Sequenom MassARRAY to investigate the association of these eighteen SNPs with colorectal neoplasm in a case-control study consisted of 1049 colorectal cancers, 283 adenomas, and 1030 controls.

Results: Two of these SNPs, rs10505477 and rs719725, showed evidence of an association in both CRC and CRA in our study population. Besides, seven SNPs (rs10808555, rs7014346, rs7837328, rs704017, rs11196172, rs4779584, and rs7229639) were significantly associated with CRC, and another one SNP rs11903757 was over-represented in CRA compared with controls. The strongest association was provided by rs11196172 (OR = 2.02, 95% CI = 1.66 - 2.46, P < 0.0001) and rs11903757 (OR = 1.96, 95% CI = 1.28 - 3.00, P = 0.0026).

Conclusion: These results suggest that some previously reported SNP associations also have impact on CRC and CRA predispositions in the Han Chinese population. A part of genetic risk to CRC is possibly mediated by susceptibility to adenomas.
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http://dx.doi.org/10.18632/oncotarget.12750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363611PMC
November 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 mining of mutated cancer genes in different clinical stages across 11 cancer types.

Oncotarget 2016 10;7(42):68270-68277

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.

Many studies have demonstrated that some genes (e.g. APC, BRAF, KRAS, PTEN, TP53) are frequently mutated in cancer, however, underlying mechanism that contributes to their high mutation frequency remains unclear. Here we used Apriori algorithm to find the frequent mutational gene sets (FMGSs) from 4,904 tumors across 11 cancer types as part of the TCGA Pan-Cancer effort and then mined the hidden association rules (ARs) within these FMGSs. Intriguingly, we found that well-known cancer driver genes such as BRAF, KRAS, PTEN, and TP53 were often co-occurred with other driver genes and FMGSs size peaked at an itemset size of 3~4 genes. Besides, the number and constitution of FMGS and ARs differed greatly among different cancers and stages. In addition, FMGS and ARs were rare in endocrine-related cancers such as breast carcinoma, ovarian cystadenocarcinoma, and thyroid carcinoma, but abundant in cancers contact directly with external environments such as skin melanoma and stomach adenocarcinoma. Furthermore, we observed more rules in stage IV than in other stages, indicating that distant metastasis needed more sophisticated gene regulatory network.
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http://dx.doi.org/10.18632/oncotarget.11392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356553PMC
October 2016

Incidence, Surgical Treatment, and Prognosis of Anorectal Melanoma From 1973 to 2011: A Population-Based SEER Analysis.

Medicine (Baltimore) 2016 Feb;95(7):e2770

From the Department of Surgical Oncology (HC, YC, YL, JH, YH, QX, KD),The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou ,Zhejiang, China); and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province) (HC, YC, YL, JH, YH, QX, WH, KD), The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Anorectal melanoma (AM) is a rare type of melanoma that accounts for 0.4% to 1.6% of total malignant melanomas. The incidence of AM increases over time, and it remains highly lethal, with a 5-year survival rate of 6% to 22%. Considering the rare nature of this disease, most studies on AM comprise isolated case reports and single-center trials, which could not provide comprehensive assessment of the disease. Therefore, we conducted a population-based study by using the Surveillance, Epidemiology, and End Results (SEER) program to provide the latest and best available evidence of AM.We extracted all cases of AM registered in the SEER database from 1973 to 2011 (April 2014 release) and calculated age-adjusted incidence. Only cases with active follow-up were included to predict factors associated with prognosis. Survival outcomes were also compared among different types of surgery.We identified 640 AM cases, which consisted of 265 rectal melanoma and 375 anal melanoma. The estimated annual incidence rates of AM per 1 million population were 0.259 in males and 0.407 in females, and it increased with advanced age and over time. Tumor stage and surgical treatment were independent predictors of survival. Results implied that surgery improved the prognosis of patients with local- and regional-stage AM but could not prolong the survival of patients with distant-stage AM. Moreover, the outcome of less extensive excision was not statistically different from that of more extensive excision.This study provides an up-to-date estimation of the incidence and prognosis of AM by using SEER data. The incidence of AM continuously increases over time, despite its rarity. This disease also exhibits poor prognosis. Thus, AM must be further investigated in future studies. We also recommend surgery as the optimal treatment for local- and regional-stage AM patients but not for those with distant metastasis.
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http://dx.doi.org/10.1097/MD.0000000000002770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998623PMC
February 2016

Tumor heterogeneity uncovered by dynamic expression of long noncoding RNA at single-cell resolution.

Cancer Genet 2015 Dec 25;208(12):581-6. Epub 2015 Sep 25.

Cancer Institute, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address:

The expression of long noncoding RNA (lncRNA) is thought to be more cell-type specific than the expression of protein-coding genes. However, the expression profile of individual cells regarding lncRNA remains to be elucidated. Here, we comprehensively investigated the pattern of lncRNA expression across five glioblastoma tumors (414 cells) and two cell lines (GBM6 and GBM8, 127 cells). We found that there were more than 1,000 lncRNAs that varied between any two cells and that there was frequent gain and loss of lncRNA expression during tumor cell proliferation, suggesting a great heterogeneity in lncRNA expression across different single cells in glioblastoma.
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http://dx.doi.org/10.1016/j.cancergen.2015.09.005DOI Listing
December 2015

Dynamics of chloroplast genomes in green plants.

Genomics 2015 Oct 21;106(4):221-31. Epub 2015 Jul 21.

Waksman Institute of Microbiology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.

Chloroplasts are essential organelles, in which genes have widely been used in the phylogenetic analysis of green plants. Here, we took advantage of the breadth of plastid genomes (cpDNAs) sequenced species to investigate their dynamic changes. Our study showed that gene rearrangements occurred more frequently in the cpDNAs of green algae than in land plants. Phylogenetic trees were generated using 55 conserved protein-coding genes including 33 genes for photosynthesis, 16 ribosomal protein genes and 6 other genes, which supported the monophyletic evolution of vascular plants, land plants, seed plants, and angiosperms. Moreover, we could show that seed plants were more closely related to bryophytes rather than pteridophytes. Furthermore, the substitution rate for cpDNA genes was calculated to be 3.3×10(-10), which was almost 10 times lower than genes of nuclear genomes, probably because of the plastid homologous recombination machinery.
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http://dx.doi.org/10.1016/j.ygeno.2015.07.004DOI Listing
October 2015

CPuORF correlates with miRNA responsive elements on protein evolutionary rates.

Biochem Biophys Res Commun 2014 Sep 19;452(1):66-71. Epub 2014 Aug 19.

Cancer Institute, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China; Zhejiang-California International Nanosystems Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address:

miRNA is increasingly being recognized as a key regulator of metabolism in animals. A wealth of evidence has suggested that miRNA mainly binds 3' UTR of mRNA and modulates the cell activities via repressing the mRNA translation. However, as the translation initiates at 5' UTR, cis elements like upstream open reading frame (uORF) resided in 5' UTR may also affect the translation efficiency or elongation. In this study, we performed a systematic analysis of miRNA responsive elements (MREs) and uORF of the same transcript in three model organisms (human, mouse, and Drosophila). Intriguingly, we found that the 3' UTR length grew with the complexity of species (human>mouse>Drosophila), in sharp contrast with the invariability of 5' UTR. Additionally, MRE number correlated well with the 3' UTR length, while uORF number showed a weak correlation with the 5' UTR length. Further, we found that human genes with conserved peptide upstream open reading frame (CPuORF) tend to have more MREs and lower evolutionary rates, which provides new insights into the correlation between UTR properties and translational control in animals.
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http://dx.doi.org/10.1016/j.bbrc.2014.08.050DOI Listing
September 2014

Adoptive antitumor immunotherapy in vitro and in vivo using genetically activated erbB2-specific T cells.

J Immunother 2014 Sep;37(7):351-9

*Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Science ‡The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang †Xuanwu Hospital, Capital Medical University, Beijing, P.R. China.

The use of human T lymphocytes genetically modified to express chimeric antigen receptors on their surfaces has emerged as a promising treatment strategy for malignant tumors. We have transfected primary human peripheral T lymphocytes with a recombinant vector carrying DNA fragments encoding anti-erbB2 scFv/Fc/CD28/CD3ζ chimeric antigen receptor using electroporation. Transfected T cells have been demonstrated to express anti-erB2 scFv/Fc on their surface and CD28/CD3ζ intracellularly. These modified T cells were able to specifically bind to erbB2 tumor-associated antigen on target tumor cells. After specific binding, modified T cells were activated to produce high levels of cytokines (not only interferon-γ but also interluekin-2) and mediate lysis of erbB2-positive human tumor cells in an antigen-specific manner. Furthermore, such genetically modified human T cells significantly delayed the growth of subcutaneous erbB2-positive human xenograft tumors after systemic administration. These preclinical studies suggest that human T cells can be modified genetically and redirected to tumors in cancer patients.
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http://dx.doi.org/10.1097/CJI.0000000000000048DOI Listing
September 2014

Flexible microRNA arm selection in rice.

Biochem Biophys Res Commun 2014 May 15;447(3):526-30. Epub 2014 Apr 15.

Institute of Crop Science, Zhejiang Key Laboratory of Crop Germplasm, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address:

MicroRNAs act at the post-transcriptional level and guide Argonaute proteins to cleave their corresponding target transcripts. However, little attention has been paid to arm selection in miRNA precursors. In this study, small RNA high-throughput sequencing data from 29 different rice libraries were pooled to investigate tissue- and abiotic stress-specific dynamic expression of miRNAs. We found that more than half of pre-miRNAs showed changes in arm selection in different tissues and/or under different abiotic stresses. Our findings suggest that miRNA selection is remarkably prevalent in plants, providing new insights into the role of miRNAs in plant growth and development.
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http://dx.doi.org/10.1016/j.bbrc.2014.04.036DOI Listing
May 2014

MicroRNA mediates DNA methylation of target genes.

Biochem Biophys Res Commun 2014 Feb 4;444(4):676-81. Epub 2014 Feb 4.

Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address:

Small RNAs represented by microRNA (miRNA) plays important roles in plant development and responds to biotic and abiotic stresses. Previous studies have placed special emphasis on gene-repression mediated by miRNA. In this work, the DNA methylation pattern of microRNA genes (MIRs) was interrogated. Full-length cDNA and EST were used to confirm the entity of pri-miRNA. In parallel, miRNA in 24 nucleotides (nt) was pooled to detect chromatin modification effect by using bisulfite sequencing data. 97 MIRs were supported by full-length cDNA and 30 more were hit by EST. Notably, methylation levels of conserved MIRs were significantly lower than the non-conserved at all contexts (CG, CHG, and CHH). Additionally, a substantial part of 24-nt miRNA was able to induce target site methylation, providing a broader perspective for researchers.
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http://dx.doi.org/10.1016/j.bbrc.2014.01.171DOI Listing
February 2014