Publications by authors named "Meng Lou"

29 Publications

  • Page 1 of 1

A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer.

Cell Death Dis 2021 Jul 7;12(7):683. Epub 2021 Jul 7.

Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.
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http://dx.doi.org/10.1038/s41419-021-03969-1DOI Listing
July 2021

A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells.

Cell 2021 Jul 21;184(15):3981-3997.e22. Epub 2021 Jun 21.

Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA. Electronic address:

A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of self-activated T cells within unperturbed tissue environments by combining high-resolution multiplexed and volumetric imaging with computational modeling. In lymph nodes, self-activated T cells produced interleukin (IL)-2, which enhanced local regulatory T cell (Treg) proliferation and inhibitory functionality. The resulting micro-domains reciprocally constrained inputs required for damaging effector responses, including CD28 co-stimulation and IL-2 signaling, constituting a negative feedback circuit. Due to these local constraints, self-activated T cells underwent transient clonal expansion, followed by rapid death ("pruning"). Computational simulations and experimental manipulations revealed the feedback machinery's quantitative limits: modest reductions in Treg micro-domain density or functionality produced non-linear breakdowns in control, enabling self-activated T cells to subvert pruning. This fine-tuned, paracrine feedback process not only enforces immune homeostasis but also establishes a sharp boundary between autoimmune and host-protective T cell responses.
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http://dx.doi.org/10.1016/j.cell.2021.05.028DOI Listing
July 2021

The ovarian carcinoma risk with the polymorphisms of CYP1B1 come from the positive selection.

Am J Transl Res 2021 15;13(5):4322-4341. Epub 2021 May 15.

Department of Gynecologic Oncology, The Affiliated Tumor Hospital of Guangxi Medical University Nanning, China.

Ovarian carcinoma is one of the major causes of gynecological cancer. This study aimed to evaluate the association of CYP1 family polymorphism with the risk of ovarian carcinoma and chemotherapy resistance. Positive selection was detected among human CYP1A1, CYP1A2, and CYP1B1, and other species. Several positive sites were detected by site models and brach-site models. Meta-analysis was conducted for the sites rs1056836 (MAF 0.39) and rs1056827 (MAF 0.36) of CYP1B1 to clarify the association between gene polymorphisms and ovarian carcinoma risk. Subgroup analysis showed the association of rs1056836 polymorphism with ovarian cancer risk among Caucasians and Asians, while all the six genetic models showed no association among African-Americans. All the six genetic models showed no association of rs1056827 polymorphism with ovarian cancer risk. The polymorphisms of rs1056836 associated with ovarian cancer risk were detected in chemotherapy-sensitive and drug-resistant ovarian cancer patients. DNA was extracted from 62 chemotherapy resistance Ovarian carcinoma tissue samples and 137 chemotherapy-sensitive ovarian carcinoma tissue samples as controls. Gene polymorphisms were genotyped using the Sequenom MassARRAY SNP approach. There was no significant association between the CYP1B1 rs1056836 polymorphism and chemotherapy resistance of ovarian cancer in all genetic models. The results suggest that rs1056836 polymorphism of gene CYP1B1 under obvious selection pressure had a significantly increased risk for ovarian carcinoma. However, it had no significant correlation with chemotherapy resistance of ovarian cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205773PMC
May 2021

DCANet: Dual contextual affinity network for mass segmentation in whole mammograms.

Med Phys 2021 Jun 1. Epub 2021 Jun 1.

School of Information Science and Engineering, Lanzhou University, Lanzhou, Gansu, China.

Purpose: Breast mass segmentation in mammograms remains a crucial yet challenging topic in computer-aided diagnosis systems. Existing algorithms mainly used mass-centered patches to achieve mass segmentation, which is time-consuming and unstable in clinical diagnosis. Therefore, we aim to directly perform fully automated mass segmentation in whole mammograms with deep learning solutions.

Methods: In this work, we propose a novel dual contextual affinity network (a.k.a., DCANet) for mass segmentation in whole mammograms. Based on the encoder-decoder structure, two lightweight yet effective contextual affinity modules including the global-guided affinity module (GAM) and the local-guided affinity module (LAM) are proposed. The former aggregates the features integrated by all positions and captures long-range contextual dependencies, aiming to enhance the feature representations of homogeneous regions. The latter emphasizes semantic information around each position and exploits contextual affinity based on the local field-of-view, aiming to improve the indistinction among heterogeneous regions.

Results: The proposed DCANet is greatly demonstrated on two public mammographic databases including the DDSM and the INbreast, achieving the Dice similarity coefficient (DSC) of 85.95% and 84.65%, respectively. Both segmentation performance and computational efficiency outperform the current state-of-the-art methods.

Conclusion: According to extensive qualitative and quantitative analyses, we believe that the proposed fully automated approach has sufficient robustness to provide fast and accurate diagnoses for possible clinical breast mass segmentation.
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http://dx.doi.org/10.1002/mp.15010DOI Listing
June 2021

Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins.

Signal Transduct Target Ther 2021 03 15;6(1):123. Epub 2021 Mar 15.

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

The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.
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http://dx.doi.org/10.1038/s41392-021-00515-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958565PMC
March 2021

Differences in Capacity of High-Amylose Resistant Starch, Whole-Grain Flour, and a Combination of Both to Modify Intestinal Responses of Male Sprague Dawley Rats Fed Moderate and High Fat Diets.

J Agric Food Chem 2020 Dec 8;68(51):15176-15185. Epub 2020 Dec 8.

Nutrition and Food Sciences/Animal Sciences, LSU AgCenter, Baton Rouge 70803, Louisiana, United States.

Gastrointestinal tract (GIT) responses to a high-amylose resistant starch (RS) product were compared to those observed when RS was combined with whole grain (WG) and to controls with low RS intake in rats fed moderate or high fat diets. Regardless of fat intake, rats fed RS or WG + RS diets had higher cecum weights, higher intestinal quantities of short chain fatty acids, and lower intestinal content pH, and their GIT cells had increased gene expression for gluconeogenesis and barrier function compared to controls. Whereas RS resulted in greater GIT content acetate and propionate and lowest pH, the WG + RS diets yielded higher butyrate. Rats fed the RS diet with MF had higher cecum weights than those fed either the RS diet with HF or the WG + RS diet with either MF or HF. Diets containing combinations of RS and other dietary fibers should be considered for RS-mediated GIT benefits.
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http://dx.doi.org/10.1021/acs.jafc.0c05285DOI Listing
December 2020

Aberrant methylation of GADD45A is associated with decreased radiosensitivity in cervical cancer through the PI3K/AKT signaling pathway.

Oncol Lett 2021 Jan 3;21(1). Epub 2020 Nov 3.

Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.

Epigenetic inactivation of GADD45A is a common occurrence in different types of cancer. However, little is known regarding its association with radiosensitivity in cervical cancer (CC). Thus, the present study aimed to investigate the association between aberrant GADD45A methylation and radiosensitivity in CC. SiHa, HeLa and CaSki CC cells were treated with 5-azacytidine (5-azaC), with or without irradiation. The expression levels of GADD45A and AKT related molecules were detected via reverse transcription-quantitative PCR and western blot analyses. The methylation status of GADD45A was assessed via methylation-specific PCR and cell proliferation assays, while clonogenic assays and flow cytometric analysis were performed to assess the function of the genes (GADD45A and AKT) in the CC cell lines. The results demonstrated that methylation of GADD45A was significantly higher in the radioresistant tissues (63.16%) compared with the radiosensitive samples (33.33%). In addition, the surviving fraction of SiHa cells following irradiation with 2 Gy was demonstrated to be highest amongst the three CC cells (CaSki, 57±9.5%; HeLa, 70±4% and SiHa, 75±10%). The survival rate of SiHa cells following treatment with 5-azaC and ionizing radiation (IR) significantly decreased as the radiation dose increased, compared with treatment with IR alone. Following overexpression of GADD45A or treatment with 5-azaC, the radiosensitivity of SiHa cells significantly increased compared with both the control vector and PBS treated groups. In addition, the AKT inhibitor, MK-2206, increased the radiosensitivity of SiHa cells. Notably, aberrant methylation of GADD45A was associated with decreased radiosensitivity in CC, and the PI3K/AKT signaling pathway was essential for radioresistance, which was mediated through downregulation of GADD45A.
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http://dx.doi.org/10.3892/ol.2020.12269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681222PMC
January 2021

Integrated Analysis of Distant Metastasis-Associated Genes and Potential Drugs in Colon Adenocarcinoma.

Front Oncol 2020 23;10:576615. Epub 2020 Oct 23.

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

Most colon adenocarcinoma (COAD) patients die of distant metastasis, though there are some therapies for metastatic COAD. However, the genes exclusively expressed in metastatic COAD remain unclear. This study aims to identify prognosis-related genes associated with distant metastasis and develop therapeutic strategies for COAD patients. Transcriptomic data from The Cancer Genome Atlas (TCGA; = 514) cohort were analyzed as a discovery dataset. Next, the data from the GEPIA database and PROGgeneV2 database were used to validate our analysis. Key genes were identified based on the differential miRNA and mRNA expression with respect to M stage. The potential drugs targeting candidate differentially expressed genes (DEGs) were also investigated. A total of 127 significantly DEGs in patients with distant metastasis compared with patients without distant metastasis were identified. Then, four prognosis-related genes (LEP, DLX2, CLSTN2, and REG3A) were selected based on clustering analysis and survival analysis. Finally, three compounds targeting the candidate DEGs, including ajmaline, TTNPB, and dydrogesterone, were predicted to be potential drugs for COAD. This study revealed that distant metastasis in COAD is associated with a specific group of genes, and three existing drugs may suppress the distant metastasis of COAD.
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http://dx.doi.org/10.3389/fonc.2020.576615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645237PMC
October 2020

The lymph node at a glance - how spatial organization optimizes the immune response.

J Cell Sci 2020 03 6;133(5). Epub 2020 Mar 6.

Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Memorial Dr, Bethesda, MD 20892, USA

A hallmark of the mammalian immune system is its ability to respond efficiently to foreign antigens without eliciting an inappropriate response to self-antigens. Furthermore, a robust immune response requires the coordination of a diverse range of cells present at low frequencies within the host. This problem is solved, in part, by concentrating antigens, antigen-presenting cells and antigen-responsive cells in lymph nodes (LNs). Beyond housing these cell types in one location, LNs are highly organized structures consisting of pre-positioned cells within well-defined microanatomical niches. In this Cell Science at a Glance article and accompanying poster, we outline the key cellular populations and components of the LN microenvironment that are present at steady state and chronicle the dynamic changes in these elements following an immune response. This review highlights the LN as a staging ground for both innate and adaptive immune responses, while providing an elegant example of how structure informs function.
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http://dx.doi.org/10.1242/jcs.241828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063836PMC
March 2020

miR-520b Promotes Breast Cancer Stemness Through Hippo/YAP Signaling Pathway.

Onco Targets Ther 2019 31;12:11691-11700. Epub 2019 Dec 31.

Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People's Republic of China.

Introduction: The breast cancer stem cells contribute to the initiation, progression, recurrence, metastasis as well as resistance of breast cancer. However, the mechanisms underlying the maintenance of breast cancer stemness have not been fully understood.

Materials And Methods: TCGA and GEO data were used for measuring miR-520b expression in breast cancer tissues. Kaplan-meier analysis was used for determining the relationship between miR-520b expression level and the prognosis of patients. Genetic manipulation was performed by lentivirus system and miR-520b inhibitor was used for knockdown of miR-520b. qRT-PCR and Western blot were employed to determine the mRNA and protein levels, respectively. The stemness and EMT (Epithelial to mesenchymal transition) were assessed by sphere-formation and transwell assay as well as the expression of the related markers. The target genes of miR-520b were identified using the online database starBase V3.0.

Results: miR-520b is upregulated in cancer tissues of breast cancer patients and predicts poor prognosis. Upregulation of miR-520b was found in breast cancer stem cells. Ectopic expression of miR-520b promotes the stemness of the breast cancer cells, conversely, depletion of miR-520b attenuates the stemness of these cells. miR-520b positively regulates Hippo/YAP signaling pathway and overexpression of LAST2 abolished the effect of miR-520b on the stemness of breast cancer cells.

Conclusion: miR-520b promotes the stemness of breast cancer patients by activating Hippo/YAP signaling via targeting LATS2.
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http://dx.doi.org/10.2147/OTT.S236607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942529PMC
December 2019

HIV-2/SIV Vpx targets a novel functional domain of STING to selectively inhibit cGAS-STING-mediated NF-κB signalling.

Nat Microbiol 2019 12 28;4(12):2552-2564. Epub 2019 Oct 28.

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

Innate immunity is the first line of host defence against pathogens. Suppression of innate immune responses is essential for the survival of all viruses. However, the interplay between innate immunity and HIV/SIV is only poorly characterized. We have discovered Vpx as a novel inhibitor of innate immune activation that associates with STING signalosomes and interferes with the nuclear translocation of NF-κB and the induction of innate immune genes. This new function of Vpx could be separated from its role in mediating degradation of the antiviral factor SAMHD1, and is conserved among diverse HIV-2/SIV Vpx. Vpx selectively suppressed cGAS-STING-mediated nuclear factor-κB signalling. Furthermore, Vpx and Vpr had complementary activities against cGAS-STING activity. Since SIV lacking both Vpx and Vpr was less pathogenic than SIV deficient for Vpr or Vpx alone, suppression of innate immunity by HIV/SIV is probably a key pathogenic determinant, making it a promising target for intervention.
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http://dx.doi.org/10.1038/s41564-019-0585-4DOI Listing
December 2019

Increased expression of Na/H exchanger isoform 1 predicts tumor aggressiveness and unfavorable prognosis in epithelial ovarian cancer.

Oncol Lett 2018 Nov 25;16(5):6713-6720. Epub 2018 Sep 25.

Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing 400030, P.R. China.

Na/H exchanger isoform 1 (NHE1), which is a regulator of intracellular and extracellular pH via ion exchange, has been demonstrated to serve an important role in cell differentiation, migration and invasion in solid tumors and hematological malignancies. However, the potential role of NHE1 in epithelial ovarian cancer (EOC) remains unclear. In the present study, the expression pattern and the prognostic value of NHE1 were investigated in EOC. EOC tissues, non-cancerous tumors and normal ovarian tissues were collected, and the expression levels of NHE1 were determined using the reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry. The expression pattern of NHE1 was also evaluated in ovarian cancer cell lines using western blotting and immunofluorescence. In addition, the association between the NHE1 expression pattern and the clinicopathological features and the clinical prognosis of patients with EOC was also analyzed. The expression levels of NHE1 were identified to be significantly increased in EOC tissues compared with non-cancerous tumors and normal ovarian tissues (P<0.05). Furthermore, the increased expression of NHE1 was associated with an advanced International Federation of Gynecology and Obstetrics stage (FIGO III-IV; P<0.001) and the presence of high-grade carcinoma (grades 2-3, P<0.001). Overexpressed NHE1 was identified as a risk factor of shorter PFS (P<0.001) and OS (P<0.001). A multivariate Cox's regression analysis revealed that NHE1 was an independent prognostic factor for the prediction of the outcome of patients with EOC. NHE1 may, therefore, serve as a potential therapeutic target to inhibit tumor aggressiveness.
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http://dx.doi.org/10.3892/ol.2018.9500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202499PMC
November 2018

Cxcr1 mediates recruitment of neutrophils and supports proliferation of tumor-initiating astrocytes in vivo.

Sci Rep 2018 09 5;8(1):13285. Epub 2018 Sep 5.

Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA.

Neutrophils are first-responders to sites of infection and tissue damage including the inflamed tumor microenvironment. Increasing evidence suggests that crosstalk between tumors and neutrophils can affect the progression of established tumors. However, there is a gap in our understanding of the early events that lead to neutrophil recruitment to oncogene-transformed cells and how these pathways alter tumor progression. Here, we use optically transparent zebrafish larvae to probe the early signals that mediate neutrophil recruitment to Kras-transformed astrocytes. We show that zebrafish larvae with impaired neutrophil function exhibit reduced proliferation of transformed astrocytes supporting a critical role for tumor-associated neutrophils in the early progression of tumorigenesis. Moreover, using mutants and pharmacological inhibition, we show that the chemokine receptor Cxcr1 promotes neutrophil recruitment, proliferation of tumor-initiating cells, and neoplastic mass formation. These findings highlight the power of the larval zebrafish system to image and probe early events in the tumor-initiating microenvironment and demonstrate the potential for neutrophil recruitment signaling pathways such as Cxcl8-Cxcr1 as targets for anti-cancer therapies.
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http://dx.doi.org/10.1038/s41598-018-31675-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125480PMC
September 2018

Long non-coding RNA LSINCT5 promotes ovarian cancer cell proliferation, migration and invasion by disrupting the CXCL12/CXCR4 signalling axis.

Oncol Lett 2018 May 12;15(5):7200-7206. Epub 2018 Mar 12.

Key Laboratory of Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing 400030, P.R. China.

Long stress-induced noncoding transcript 5 (LSINCT5) is a member of the LSINCT family, members of which are expressed during stress-induced cell formation and have also been reported to promote cancer progression. In the present study, the association between LSINCT5 expression and clinical significance was investigated and the biological function of LSINCT5 in epithelial ovarian cancer (EOC) was explored. LSINCT5 expression was examined in EOC tissues by reverse transcription-quantitative polymerase chain reaction and its association with clinicopathological factors was analysed. Cell proliferation, migration and invasion tests were performed to observe the role of LSINCT5 in human ovarian cancer cell lines . The negative control (NC) and siLSINCT5 SKOV3 cells were treated with chemokine ligand 12 (CXCL12) and their proliferation, migration and invasion activities were examined. LSINCT5 was overexpressed in EOC compared with normal ovarian tissue. LSINCT5 expression was significantly associated with the International Federation of Gynecologists and Obstetricians cancer stage and the presence of lymphatic metastases. Silencing LSINCT5 significantly reduced the expression of chemokine receptor 4 (CXCR4) and inhibited SKOV3 cell proliferation, migration and invasion, however the CXCL12 expression level had no significant change. When NC and siLSINCT5-SKOV3 cells were treated with CXCL12, the proliferation and invasion ability were significantly enhanced. The migration ability of the siLSINCT5-SKOV3 cells was also significantly enhanced. The present study indicated that LSINCT5 serves an important role in ovarian cancer metastasis by regulating the CXCL12/CXCR4 signalling axis, suggesting that this pathway may be a potential target for the treatment of patients with EOC.
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http://dx.doi.org/10.3892/ol.2018.8241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943677PMC
May 2018

Assembly of CRISPR ribonucleoproteins with biotinylated oligonucleotides via an RNA aptamer for precise gene editing.

Nat Commun 2017 11 23;8(1):1711. Epub 2017 Nov 23.

Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA.

Writing specific DNA sequences into the human genome is challenging with non-viral gene-editing reagents, since most of the edited sequences contain various imprecise insertions or deletions. We developed a modular RNA aptamer-streptavidin strategy, termed S1mplex, to complex CRISPR-Cas9 ribonucleoproteins with a nucleic acid donor template, as well as other biotinylated molecules such as quantum dots. In human cells, tailored S1mplexes increase the ratio of precisely edited to imprecisely edited alleles up to 18-fold higher than standard gene-editing methods, and enrich cell populations containing multiplexed precise edits up to 42-fold. These advances with versatile, preassembled reagents could greatly reduce the time and cost of in vitro or ex vivo gene-editing applications in precision medicine and drug discovery and aid in the development of increased and serial dosing regimens for somatic gene editing in vivo.
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http://dx.doi.org/10.1038/s41467-017-01875-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700129PMC
November 2017

Physical interaction between human ribonucleotide reductase large subunit and thioredoxin increases colorectal cancer malignancy.

J Biol Chem 2017 06 14;292(22):9136-9149. Epub 2017 Apr 14.

From the Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China,

Ribonucleotide reductase (RR) is the rate-limiting enzyme in DNA synthesis, catalyzing the reduction of ribonucleotides to deoxyribonucleotides. During each enzymatic turnover, reduction of the active site disulfide in the catalytic large subunit is performed by a pair of shuttle cysteine residues in its C-terminal tail. Thioredoxin (Trx) and glutaredoxin (Grx) are ubiquitous redox proteins, catalyzing thiol-disulfide exchange reactions. Here, immunohistochemical examination of clinical colorectal cancer (CRC) specimens revealed that human thioredoxin1 (hTrx1), but not human glutaredoxin1 (hGrx1), was up-regulated along with human RR large subunit (RRM1) in cancer tissues, and the expression levels of both proteins were correlated with cancer malignancy stage. Ectopically expressed hTrx1 significantly increased RR activity, DNA synthesis, and cell proliferation and migration. Importantly, inhibition of both hTrx1 and RRM1 produced a synergistic anticancer effect in CRC cells and xenograft mice. Furthermore, hTrx1 rather than hGrx1 was the efficient reductase for RRM1 regeneration. We also observed a direct protein-protein interaction between RRM1 and hTrx1 in CRC cells. Interestingly, besides the known two conserved cysteines, a third cysteine (Cys) in the RRM1 C terminus was essential for RRM1 regeneration and binding to hTrx1, whereas both Cys and Cys in hTrx1 played a counterpart role. Our findings suggest that the up-regulated RRM1 and hTrx1 in CRC directly interact with each other and promote RR activity, resulting in enhanced DNA synthesis and cancer malignancy. We propose that the RRM1-hTrx1 interaction might be a novel potential therapeutic target for cancer treatment.
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http://dx.doi.org/10.1074/jbc.M117.783365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454097PMC
June 2017

Silencing nc886, a Non-Coding RNA, Induces Apoptosis of Human Endometrial Cancer Cells-1A In Vitro.

Med Sci Monit 2017 Mar 16;23:1317-1324. Epub 2017 Mar 16.

Department of Obstetrics and Gynecology, The 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).

BACKGROUND The role that nc886, a non-coding microRNA, plays in human endometrial cancer is unknown. The present study aimed to describe the functional role of nc886 in human endometrial cancer-1A (HEC-1A) cell line, which may provide another target for human endometrial cancer treatment. MATERIAL AND METHODS The expression levels of nv886 in normal human endometrial tissue and the early phase and late phase of human endometrial cancer tissues were determined and compared by fluorescence in situ hybridization (FISH). Small interference RNA (siRNA) was used to inhibit nc886, and cell proliferation was evaluated with the MTT test. mRNA levels of PKR, NF-κB, vascular endothelial growth factor (VEGF), and caspase-3 were determined against glyceraldehyde 3-phosphate dehydrogenase (GAPDH between the HEC-1A control group and the silenced group (nc886 silenced with siRNA) by real-time reverse transcription polymerase chain reaction (RT-PCR). The protein levels of PKR (total and phosphorylated form), NF-κB, VEGF, and caspase-3 were determined against GAPDH by Western blotting, and cell apoptosis was determined by flow cytometry. RESULTS Our results indicated that a higher level of nc886 was expressed in the late phase of human endometrial cancer tissue, less than in the early phase but still higher than in normal human endometrial tissue. After nc886 was silenced, protein levels of p-PKR (phosphorylated PKR) and caspase-3 were increased, whereas NF-κB and VEGF were decreased. CONCLUSIONS The rate of apoptosis in the silenced group was increased and the rate of cell proliferation was slower in comparison to the control.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365049PMC
http://dx.doi.org/10.12659/msm.900320DOI Listing
March 2017

ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG.

Biochim Biophys Acta 2016 Apr 24;1859(4):612-26. Epub 2016 Feb 24.

Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address:

Background: N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), an alkylating agent and an environmental carcinogen, causes DNA lesions and even carcinomas. DNA damage responses induced by MNNG activate various DNA repair genes and related signaling pathways. The present study aimed to investigate the regulatory mechanisms of human RR small subunit M2 (hRRM2) in response to MNNG.

Results: In this study, we demonstrated that the RRM2 gene was transactivated by MNNG exposure more strongly than the other small subunit, p53R2. The upregulated RRM2 translocated to the nucleus for DNA repair. Further study showed that E2F3 transactivated RRM2 expression by directly binding to its promoter after MNNG exposure. The transactivation was enhanced by the upregulation of NFY, which bound to the RRM2 promoter adjacent to the E2F3 binding site and interacted with E2F3. In response to MNNG treatment, E2F3 accumulated mainly through its phosphorylation at S124 and was dependent on ATR-CHK1 signaling. In comparison, p53R2 played a relatively weaker role in the MNNG-induced DNA damage response, and its transcription was regulated by the ATR-CHK2-E2F1/p53 pathway.

Conclusions: We suggest that MNNG-stimulated ATR/CHK1 signaling stabilizes E2F3 by S124 phosphorylation, and then E2F3 together with NFY co-transactivate RRM2 expression for DNA repair.

General Significance: We propose a new mechanism for RRM2 regulation to maintain genome stability in response to environmental chemical carcinogens.
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http://dx.doi.org/10.1016/j.bbagrm.2016.02.012DOI Listing
April 2016

Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein.

Biochem Pharmacol 2016 Mar 13;103:118-28. Epub 2016 Jan 13.

Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address:

Chronic hepatitis B virus (HBV) infection is a key factor for hepatocellular carcinoma worldwide. Ribonucleotide reductase (RR) regulates the deoxyribonucleoside triphosphates biosynthesis and serves as a target for anti-cancer therapy. Here, we demonstrate that RR is essential for HBV replication and the viral covalently-closed-circular DNA (cccDNA) synthesis in host liver cells. By performing computer-assisted virtual screening against the crystal structure of RR small subunit M2 (RRM2), osalmid, was identified as a potential RRM2-targeting compound. Osalmid was shown to be 10-fold more active in inhibiting RR activity than hydroxyurea, and significantly inhibited HBV DNA and cccDNA synthesis in HepG2.2.15 cells. In contrast, hydroxyurea and the RR large subunit (RRM1)-inhibitory drug gemcitabine showed little selective activity against HBV replication. In addition, osalmid also was shown to possess potent activity against a 3TC-resistant HBV strain, suggesting utility in treating drug-resistant HBV infections. Interestingly, osalmid showed synergistic effects with lamivudine (3TC) in vitro and in vivo without significant toxicity, and was shown to inhibit RR activity in vivo, thus verifying its in vivo function. Furthermore, 4-cyclopropyl-2-fluoro-N-(4-hydroxyphenyl) benzamide (YZ51), a novel derivative of osalmid, showed higher efficacy than osalmid with more potent RR inhibitory activity. These results suggest that RRM2 might be targeted for HBV inhibition, and the RRM2-targeting compound osalmid and its derivative YZ51 could be a novel class of anti-HBV candidates with potential use for hepatitis B and HBV-related HCC treatment.
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http://dx.doi.org/10.1016/j.bcp.2016.01.003DOI Listing
March 2016

High-Content Analysis of CRISPR-Cas9 Gene-Edited Human Embryonic Stem Cells.

Stem Cell Reports 2016 Jan;6(1):109-20

Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Medical History and Bioethics, University of Wisconsin-Madison, Madison, WI 53715, USA. Electronic address:

CRISPR-Cas9 gene editing of human cells and tissues holds much promise to advance medicine and biology, but standard editing methods require weeks to months of reagent preparation and selection where much or all of the initial edited samples are destroyed during analysis. ArrayEdit, a simple approach utilizing surface-modified multiwell plates containing one-pot transcribed single-guide RNAs, separates thousands of edited cell populations for automated, live, high-content imaging and analysis. The approach lowers the time and cost of gene editing and produces edited human embryonic stem cells at high efficiencies. Edited genes can be expressed in both pluripotent stem cells and differentiated cells. This preclinical platform adds important capabilities to observe editing and selection in situ within complex structures generated by human cells, ultimately enabling optical and other molecular perturbations in the editing workflow that could refine the specificity and versatility of gene editing.
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http://dx.doi.org/10.1016/j.stemcr.2015.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720027PMC
January 2016

Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis.

Tumour Biol 2015 Jun 1;36(6):4833-42. Epub 2015 Feb 1.

Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Ribonucleotide reductase large subunit M1 (RRM1) forms a holoenzyme with small subunits to provide deoxyribonucleotides for DNA synthesis and cell proliferation. Here, we reported a non-RR role of the catalytic subunit protein RRM1 and related pathway in inhibiting colorectal cancer (CRC) metastasis. Ectopic overexpression of the wild-type RRM1, and importantly, its Y738F mutant that lacks RR enzymatic activity, prevented the migration and invasion of CRC cells by promoting phosphatase and tensin homolog on chromosome 10 (PTEN) transactivation. Furthermore, overexpression of the wild-type and RR-inactive mutant RRM1 similarly reduced the phosphorylation of Akt and increased the E-cadherin expression in CRC cells, which were blocked by PTEN knockdown attenuation. Examination of clinical CRC specimens demonstrated that both RRM1 protein expression and RR activity were elevated in most cancer tissues compared to the paired normal tissues. However, while RR activity did not change significantly in different cancer stages, the RRM1 protein level was significantly increased at stages T1-3 but decreased at stage T4, in parallel with the PTEN expression level and negatively correlated with invasion and liver metastasis. Thus, we propose that RRM1 protein can inhibit CRC invasion and metastasis at the advanced stage by regulating PTEN transactivation and its downstream pathways in addition to forming an RR holoenzyme for supporting cancer proliferation. Understanding of the seemingly contrary dual roles of RRM1 protein may further help to explain the complex mechanisms by which this key enzyme and its components are involved in cancer development.
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http://dx.doi.org/10.1007/s13277-015-3137-4DOI Listing
June 2015

Clinicopathological significance of steroidogenic factor-1 expression in ovarian cancer versus ovarian sex cord stromal tumor.

Tumour Biol 2015 Mar 22;36(3):1429-35. Epub 2015 Jan 22.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China.

The significance of steroidogenic factor-1 (SF-1) in human ovarian tumor has not been fully investigated. The purposes of this study are to provide a meta-analysis for SF-1 and to determine whether SF-1 is associated with ovarian tumor progression and clinicopathological characteristics. A detailed literature search was made for related research publications written in English. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data was performed, and odds ratio (OR) and corresponding confidence intervals (CIs) were calculated and summarized respectively. Final analysis from seven eligible studies was performed. Aberrant SF-1 expression was significantly lower in ovarian cancer compared to that of normal ovarian tissue (OR = 0.02, 95% CI = 0.00-0.16, p = 0.0002). However, SF-1 protein expression was not significantly different between benign and malignant ovarian tumors (p = 0.35). Interestingly, aberrant SF-1 expression was significantly higher in ovarian sex cord stromal tumors than that of ovarian cancer (OR = 0.00, 95% CI = 0.00-0.01, p < 0.00001). The results of this meta-analysis suggest that SF-1 may play an important role in ovarian cancer initiation and progression. Moreover, SF-1 expression may serve as a marker in the differential diagnosis between ovarian sex cord stromal tumors and ovarian cancer.
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http://dx.doi.org/10.1007/s13277-014-2187-3DOI Listing
March 2015

Clinical responses to focused ultrasound applied to women with vulval intraepithelial neoplasia.

J Ultrasound Med 2014 Nov;33(11):1903-8

Department of Obstetrics and Gynecology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Y.J., J.W., L.T., M.Lu., M.Lo.); and Department of Pathology, College of Basic Medicine (M.X.), and Biomedical Engineering College (C.L.), Chongqing Medical University, Chongqing, China.

Objectives: Focused ultrasound waves penetrate superficial tissues and are aimed toward the target tissues at specific depths to exert their biological effects. Focused ultrasound has been applied for a number of clinical indications, including vulval dystrophies and low-grade vulval disease. This study aimed to assess the efficacy and safety of focused ultrasound treatment of high-grade vulval intraepithelial neoplasia (VIN).

Methods: Eighteen women with high-grade VIN were recruited and treated with focused ultrasound. During each posttreatment follow-up, the safety of, side effects of, and clinical responses to focused ultrasound were evaluated by a standardized protocol, including symptoms, clinical appearance, and histologic findings.

Results: All patients completed the designed follow-ups. In most cases, superficial mild to moderate swelling and blisters were seen in the focused ultrasound-treated skin but not in adjacent normal skin. Of the 18 patients, 16 showed complete histologic regression and resolution of symptoms 6 months after treatment. Of the other 2 patients, 1 showed complete regression after a second focused ultrasound treatment. The other patient did not respond to the focused ultrasound treatment and underwent a partial vulvectomy 6 months after treatment. None of the patients developed invasive carcinoma of the vulva during the follow-up period. One patient had local pruritus that was not alleviated by anti-inflammatory medication and local care.

Conclusions: The complete responses observed in women with high-grade VIN treated by focused ultrasound, together with the preservation of adjacent normal tissue, suggest that focused ultrasound may be considered for treatment of high-grade VIN.
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http://dx.doi.org/10.7863/ultra.33.11.1903DOI Listing
November 2014

Gemcitabine and carboplatin demonstrate synergistic cytotoxicity in cervical cancer cells by inhibiting DNA synthesis and increasing cell apoptosis.

Onco Targets Ther 2013 25;6:1707-17. Epub 2013 Nov 25.

Department of Gynecological Oncology, Ningbo Women and Children's Hospital, Ningbo, People's Republic of China.

Background: The present study aims to investigate the subunit expression and enzyme activity of ribonucleotide reductase in cervical cancer patients, and detect the combined effect of the ribonucleotide reductase inhibitor gemcitabine and the chemotherapeutic agent carboplatin on cervical cancer cell lines.

Methods: Using quantitative reverse transcription polymerase chain reaction, Western blotting, and cytidine 5'-diphosphate reduction assays, we tested the expression and activity of ribonucleotide reductase in cervical cancer patients. The antitumor activity of gemcitabine and/or carboplatin treatments to SiHa and CaSki human cervical cancer cell lines were assessed by Cell Counting Kit-8 viability assay, EdU incorporation assay, immunofluorescence assay, flow cytometry assay, and Western blotting methods. Additionally, synergistic efficacy was quantitatively analyzed using a combination index based on the Chou-Talalay method.

Results: The mRNA levels of three ribonucleotide reductase subunits were all upregulated in the cervical cancer tissues compared with normal tissues (P<0.0001). Consistently, the protein expression and enzyme activity of ribonucleotide reductase were also increased in the cervical cancer tissues. Interestingly, gemcitabine inhibited DNA synthesis and carboplatin induced DNA damage. Further, the combined drug regime had a significant synergistic effect on inhibiting cervical cancer cell viability (log10[combination index] <0) via enhanced DNA damage and cell apoptosis.

Conclusion: The expression and activity of ribonucleotide reductase was increased in cervical cancer. Our study demonstrated the synergistic cytotoxicity of gemcitabine and carboplatin, through inhibiting DNA synthesis and increasing cell apoptosis in cervical cancer cell lines. This evidence might provide a rational clue of their combined application to improve cervical cancer treatment.
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http://dx.doi.org/10.2147/OTT.S54217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848983PMC
December 2013

The conserved Lys-95 charged residue cluster is critical for the homodimerization and enzyme activity of human ribonucleotide reductase small subunit M2.

J Biol Chem 2014 Jan 19;289(2):909-20. Epub 2013 Nov 19.

From the Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.

Ribonucleotide reductase (RR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides for DNA synthesis. Human RR small subunit M2 exists in a homodimer form. However, the importance of the dimer form to the enzyme and the related mechanism remain unclear. In this study, we tried to identify the interfacial residues that may mediate the assembly of M2 homodimer by computational alanine scanning based on the x-ray crystal structure. Co-immunoprecipitation, size exclusion chromatography, and RR activity assays showed that the K95E mutation in M2 resulted in dimer disassembly and enzyme activity inhibition. In comparison, the charge-exchanging double mutation of K95E and E98K recovered the dimerization and activity. Structural comparisons suggested that a conserved cluster of charged residues, including Lys-95, Glu-98, Glu-105, and Glu-174, at the interface may function as an ionic lock for M2 homodimer. Although the measurements of the radical and iron contents showed that the monomer (the K95E mutant) was capable of generating the diiron and tyrosyl radical cofactor, co-immunoprecipitation and competitive enzyme inhibition assays indicated that the disassembly of M2 dimer reduced its interaction with the large subunit M1. In addition, the immunofluorescent and fusion protein-fluorescent imaging analyses showed that the dissociation of M2 dimer altered its subcellular localization. Finally, the transfection of the wild-type M2 but not the K95E mutant rescued the G1/S phase cell cycle arrest and cell growth inhibition caused by the siRNA knockdown of M2. Thus, the conserved Lys-95 charged residue cluster is critical for human RR M2 homodimerization, which is indispensable to constitute an active holoenzyme and function in cells.
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http://dx.doi.org/10.1074/jbc.M113.524546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887214PMC
January 2014

Interferon regulatory factor 1 transactivates expression of human DNA polymerase η in response to carcinogen N-methyl-N'-nitro-N-nitrosoguanidine.

J Biol Chem 2012 Apr 24;287(16):12622-33. Epub 2012 Feb 24.

Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.

DNA polymerase η (Polη) implements translesion DNA synthesis but has low fidelity in replication. We have previously shown that Polη plays an important role in the genesis of nontargeted mutations at undamaged DNA sites in cells exposed to the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Here, we report that MNNG-induced Polη expression in an interferon regulatory factor 1 (IRF1)-dependent manner in human cells. Mutagenesis analysis showed that four critical residues (Arg-82, Cys-83, Asn-86, and Ser-87) located in the IRF family conserved DNA binding domain-helix α3 were involved in DNA binding and POLH transactivation by IRF1. Furthermore, Polη up-regulation induced by IRF1 was responsible for the increase of mutation frequency in a SupF shuttle plasmid replicated in the MNNG-exposed cells. Interestingly, IRF1 was acetylated by the histone acetyltransferase CBP in these cells. Lys → Arg substitution revealed that Lys-78 of helix α3 was the major acetylation site, and the IRF1-K78R mutation partially inhibited DNA binding and its transcriptional activity. Thus, we propose that IRF1 activation is responsible for MNNG-induced Polη up-regulation, which contributes to mutagenesis and ultimately carcinogenesis in cells.
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http://dx.doi.org/10.1074/jbc.M111.313429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339973PMC
April 2012

Spectrum of p53 tumor suppressor gene mutations and breast cancer survival.

Breast Cancer Res Treat 2004 Jan;83(1):57-66

Department of Ophthalmology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.

Context: p53 mutation is associated with poor prognosis in breast cancer patients. Mutations in different structural and functional domains of p53 have different effects on its biological activities. Nevertheless, few studies have examined the full spectrum of p53 gene mutations in relation to breast cancer survival.

Objective: To evaluate the prognostic significance of the types, localizations, and multiplicity of p53 gene mutations in breast cancer patients.

Design, Setting, And Participants: Prospective cohort study of a consecutive series of 271 women with histologically confirmed primary breast cancer who underwent breast resection at the Jackson Memorial Hospital, Miami, FL, between 1984 and 1986. Main outcome measures. Ten year overall and breast-cancer-specific deaths.

Results: After adjustment for tumor stage, treatment regimen, and the number of mutations, patients with p53 mutations had significantly greater breast-cancer-specific mortality than did patients without p53 mutations (hazard ratio = 2.86; 95% confidence interval: 1.15-7.11). Further analysis of mutation characteristics showed that patients with the following mutations had significantly poorer breast cancer disease-free survival: silent/missense mixed mutations (7.95; 1.28-49.62), nonsense mutations (9.43; 1.29-69.12), transitions (3.79; 1.46-9.88), mutations in which guanine changed (3.32; 1.01-10.35), and mutations on exon 7 (6.46; 1.78-23.45).

Conclusions: Breast-cancer-specific and all-cause mortality are increased in female breast cancer patients with the following p53 mutation characteristics: silent and missense mixed mutations, transitional mutations, mutations in which guanine changed, mutations on exon 7, or multiple mutations occurring within 60 codons. These findings indicate that not just p53 mutation per se but the full spectrum (i.e., different types, locations, and numbers) of p53 mutation needs to be examined when it is used as a prognostic marker of survival in breast cancer patients.
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http://dx.doi.org/10.1023/B:BREA.0000010699.53742.60DOI Listing
January 2004

Prevalence and spectrum of p53 mutations in white Hispanic and non-Hispanic women with breast cancer.

Breast Cancer Res Treat 2003 Sep;81(1):53-60

Department of Ophthalmology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.

Hispanic women differ from non-Hispanics in breast cancer incidence, stage at diagnosis, and survival. Ethnic differences in genetic makeup, reproductive patterns, diet, socioeconomic status, physical activity, and other unidentified cultural factors may be responsible for the disparity. This study investigated occurrences of p53 tumor suppressor gene mutations in South Florida white Hispanic and white non-Hispanic women with primary breast cancer. Tumor tissues were obtained from a consecutive series of women with breast cancer who underwent breast resection at the Jackson Memorial Hospital, Miami, Florida between 1984 and 1986. A total of 231 women with primary breast cancer, aged 31-85 years, were included in the study. Among them, 64 (27.7%) were white Hispanic and 167 (72.3%) were white non-Hispanic. The majority of the patients were white non-Hispanics (72.3%). Compared to white non-Hispanics, however, white Hispanics had significantly higher proportions of tumors larger than 2 cm (53.1% v.s. 28.7%, p = 0.00) as well as larger tumor size at diagnosis (mean: 4.2 v.s. 3.0 cm, p = 0.00). The p53 gene mutation rate was significantly lower in white Hispanics than in white non-Hispanics (51.6% v.s. 70.7%, p = 0.01). Furthermore, among node-negative breast cancer patients, after adjustment for tumor size at diagnosis, logistic regression results showed that white Hispanics were 71% less likely than white non-Hispanics to carry p53 mutations (OR = 0.29 and 95% CI = 0.09-0.91). We conclude that white Hispanic women with breast cancer might have lower p53 gene mutation prevalence than white non-Hispanic women.
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http://dx.doi.org/10.1023/A:1025422905655DOI Listing
September 2003

Mutations in the p53 tumor suppressor gene and early onset breast cancer.

Cancer Biol Ther 2002 Jan-Feb;1(1):31-6

Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Room 6141, Baltimore, Maryland 21205, USA.

Among breast cancer patients p53 gene mutation is associated with a poor prognosis. Young women with breast cancer are more likely than older women to have a poor prognosis, but whether p53 gene mutation plays a role in breast cancer in young women is not clear. This study identified 199 breast cancer patients and tested the hypothesis that p53 gene mutation was associated with early onset breast cancer. Patients with p53 gene mutations were 3-times more likely to have an early onset breast cancer (age < or = 40 years at diagnosis) than those without p53 mutations (OR = 3.05, 95% CI = 1.10-8.45). Patients with both missense and silent mutations were 7-times more likely to have a diagnosis of early onset breast cancer (OR = 7.56, 95% CI = 2.22-25.8). Patients with mutations in exon 8 of the p53 gene were 6-times more likely to be diagnosed with early onset breast cancer (OR = 6.48, 95% CI = 1.37-30.6). These findings suggest that p53 gene mutation may hasten the onset of female breast cancer.
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http://dx.doi.org/10.4161/cbt.1.1.37DOI Listing
December 2002