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ABSTRACT: BACKGROUND: The oncogenic roles contributed by the Akt/PKB kinase family remain controversial and presumably depend on cell context, but are perceived to be modulated by an interplay and net balance between various isoforms. This study is intended to decipher whether distinct Akt kinase isoforms exert either redundant or unique functions in regulating neoplastic features of breast cancer cells, including epithelial-mesenchymal transition (EMT), cell motility, and stem/progenitor cell expansion. RESULTS: We demonstrate that overactivation of Akt signaling in nonmalignant MCF10A cells and in primary cultures of normal human mammary epithelial tissue results in previously unreported inhibitory effects on EMT, cell motility and stem/progenitor cell expansion. Importantly, this effect is largely redundant and independent of Akt isoform types. However, using a series of isogenic cell lines derived from MCF-10A cells but exhibiting varying stages of progressive tumorigenesis, we observe that this inhibition of neoplastic behavior can be reversed in epithelial cells that have advanced to a highly malignant state. In contrast to the tumor suppressive properties of Akt, activated Akt signaling in MCF10A cells can rescue cell viability upon treatment with cytotoxic agents. This feature is regarded as tumor-promoting. CONCLUSION: We demonstrate that Akt signaling conveys novel dichotomy effects in which its oncogenic properties contributes mainly to sustaining cell viability, as opposed to the its tumor suppressing effects, which are mediated by repressing EMT, cell motility, and stem/progenitor cell expansion. While the former exerts a tumor-enhancing effect, the latter merely acts as a safeguard by restraining epithelial cells at the primary sites until metastatic spread can be moved forward, a process that is presumably dictated by the permissive tumor microenvironment or additional oncogenic insults.
Molecular Cancer 08/2012; 11(1):61. · 3.99 Impact Factor
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ABSTRACT: The cis-acting promoter element responsible for epigenetic silencing of retinoic acid receptor responder 1 (RARRES1) by methylation is unclear. Likewise, how aberrant methylation interplays effectors and thus affects breast neoplastic features remains largely unknown.
We first compared methylation occurring at the sequences (-664~+420) flanking the RARRES1 promoter in primary breast carcinomas to that in adjacent benign tissues. Surprisingly, tumor cores displayed significantly elevated methylation occurring solely at the upstream region (-664~-86), while the downstream element (-85~+420) proximal to the transcriptional start site (+1) remained largely unchanged. Yet, hypermethylation at the former did not result in appreciable silencing effect. In contrast, the proximal sequence displayed full promoter activity and methylation of which remarkably silenced RARRES1 transcription. This phenomenon was recapitulated in breast cancer cell lines, in which methylation at the proximal region strikingly coincided with downregulation. We also discovered that CTCF occupancy was enriched at the unmethylayed promoter bound with transcription-active histone markings. Furthermore, knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state. Moreover, RARRES1 restoration not only impeded cell invasion but also promoted death induced by chemotherapeutic agents, denoting its tumor suppressive effect. Its role of attenuating invasion agreed with data generated from clinical specimens revealing that RARRES1 was generally downregulated in metastatic lymph nodes compared to the tumor cores.
This report delineated silencing of RARRES1 by hypermethylation is occurring at a proximal promoter element and is associated with a loss of binding to CTCF, an activator for RARRES1 expression. We also revealed the tumor suppressive roles exerted by RARRES1 in part by promoting breast epithelial cell death and by impeding cell invasion that is an important property for metastatic spread.
PLoS ONE 01/2012; 7(5):e36891. · 4.09 Impact Factor
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Rulong Shen,
Sandya Liyanarachchi,
Wei Li,
Paul E Wakely,
Motoyasu Saji,
Jie Huang,
Rebecca Nagy,
Tisha Farrell,
Matthew D Ringel,
Albert de la Chapelle,
Richard T Kloos,
Huiling He
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ABSTRACT: MicroRNA (miR) expression signatures are proposed to be able to differentiate thyroid cancer from benign thyroid lesions. We selected eight miRs (miR-146b, -221, -187, -197, -346, -30d, -138, and -302c) to examine the potential use of miRs to supplement diagnostic cytology in cases designated as "atypia of undetermined significance."
miR expression was measured in thyroid fine needle aspiration (FNA) specimens by quantitative polymerase chain reaction. Gene expression analyses and linear discriminant analysis (LDA) were performed in a training sample set (n=60) to obtain a classification rule to predict FNA cases as benign or malignant. The predictions were cross-validated by comparing with the corresponding histological diagnoses. A validation sample set (n=68) was further tested with the established four-miR LDA classification rule.
A set of four miRs (miR-146b, -221, -187, and -30d) was identified that could differentiate malignant from benign lesions. A four-miR LDA classification rule was obtained and used to predict FNA cases as benign or malignant. For the training sample set, we obtained a diagnostic accuracy of 93.3%, sensitivity of 93.2%, specificity of 93.8%, positive predictive value (PPV) of 0.98, and negative predictive value (NPV) of 0.83. For the validation sample set, we obtained a diagnostic accuracy of 85.3%, sensitivity of 88.9%, specificity of 78.3%, PPV of 0.89, and NPV of 0.78. For the 30 atypia cases in the validation sample set, we obtained a diagnostic accuracy of 73.3%, sensitivity of 63.6%, specificity of 78.9%, PPV of 0.64, and NPV of 0.79. Based on the miR predictions, we classified the atypia cases predicted as "malignant" into "high risk" and those predicted as "benign" into "low risk" categories. While thyroid carcinomas, particularly papillary thyroid carcinomas (PTCs), were relatively enriched in the high-risk category, this particular miR panel is subject to inaccurate results in follicular neoplasias in atypia cases.
We demonstrate that miR amplification from FNA samples is feasible and that the particular four miR profile in this study can identify PTCs. However, further refinement is required for application to FNA cytology of "atypia of undetermined significance" cases due to low accuracy in classifying follicular neoplasias.
Thyroid: official journal of the American Thyroid Association 12/2011; 22(1):9-16. · 2.60 Impact Factor
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ABSTRACT: The performance of the Hybrid Capture 2 (HC2) test for human papilloma virus (HPV) detection depends on the prevalence of infection. However, the current HC2 manufacturer recommended interpretative algorithm is the same for all women. This test, which may be particularly useful in perimenopausal and postmenopausal women given the morphologic complexity of their Pap tests, could be affected by the overall lower prevalence of HPV infection in this age group. We investigated HC2 equivocal and weakly positive HPV tests in women 50 years and older and the detection of high-grade dysplasia (CIN2+) on their follow-up specimens. All HC2 test data from 1,067 consecutive specimens and 85 additional specimens from women ≥ 50-years-old with equivocal and weakly positive HC2 were analyzed. Follow-up specimens from women with HC2 tests within these ranges were reviewed. No CIN2+ was found on follow-up of 49 cases of women ≥ 50 with equivocal or weakly positive HC2 results. The current HC2 algorithm resulted in "positive" reports in 63% of specimens with initial equivocal HC2 due to retests mostly within the equivocal range. These results suggest that women 50 years and older may benefit from higher HC2 thresholds. The test could also be reported as HC2 values (RLU/CO) to be interpreted in view of risk factors.
Diagnostic Cytopathology 05/2011; 40(8):708-12. · 1.16 Impact Factor
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Tao Zuo,
Ta-Ming Liu,
Xun Lan,
Yu-I Weng, Rulong Shen,
Fei Gu,
Yi-Wen Huang,
Sandya Liyanarachchi,
Daniel E Deatherage,
Pei-Yin Hsu,
Cenny Taslim,
Bhuvaneswari Ramaswamy,
Charles L Shapiro,
Huey-Jen L Lin,
Alfred S L Cheng,
Victor X Jin,
Tim H-M Huang
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ABSTRACT: Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future.
Cancer Research 01/2011; 71(5):1752-62. · 7.86 Impact Factor
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De-Tao Yin,
Qien Wang,
Li Chen,
Meng-Yao Liu,
Chunhua Han,
Qingtao Yan, Rulong Shen,
Gang He,
Wenrui Duan,
Jian-Jian Li,
Altaf Wani,
Jian-Xin Gao
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ABSTRACT: DNA damage response (DDR) is an intrinsic barrier of cell to tumorigenesis initiated by genotoxic agents. However, the mechanisms underlying the DDR are not completely understood despite of extensive investigation. Recently, we have reported that ectopic expression of germline stem cell gene PIWIL2 is associated with tumor stem cell development, although the underlying mechanisms are largely unknown. Here we show that PIWIL2 is required for the repair of DNA-damage induced by various types of genotoxic agents. Upon ultraviolet (UV) irradiation, silenced PIWIL2 gene in normal human fibroblasts was transiently activated after treatment with UV light. This activation was associated with DNA repair, because Piwil2-deficienct mouse embryonic fibroblasts (mili(-/-) MEFs) were defective in cyclobutane pyrimidine dimers (CPD) repair after UV treatment. As a result, the UV-treated mili(-/-) MEFs were more susceptible to apoptosis, as characterized by increased levels of DNA damage-associated apoptotic proteins, such as active caspase-3, cleaved Poly (ADP-ribose) polymerase (PARP) and Bik. The impaired DNA repair in the mili(-/-) MEFs was associated with the reductions of histone H3 acetylation and chromatin relaxation, although the DDR pathway downstream chromatin relaxation appeared not to be directly affected by Piwil2. Moreover, guanine-guanine (Pt-[GG]) and double strand break (DSB) repair were also defective in the mili(-/-) MEFs treated by genotoxic chemicals Cisplatin and ionizing radiation (IR), respectively. The results indicate that Piwil2 can mediate DNA repair through an axis of Piwil2 → histone acetylation → chromatin relaxation upstream DDR pathways. The findings reveal a new role for Piwil2 in DNA repair and suggest that Piwil2 may act as a gatekeeper against DNA damage-mediated tumorigenesis.
PLoS ONE 01/2011; 6(11):e27154. · 4.09 Impact Factor
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De-Tao Yin,
Qien Wang,
Li Chen,
Meng-Yao Liu,
Chunhua Han,
Qingtao Yan, Rulong Shen,
Gang He,
Wenrui Duan,
Jian-Jian Li,
Altaf Wani,
Jian-Xin Gao
PLoS ONE 01/2011; 6(11). · 4.09 Impact Factor
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ABSTRACT: Generally, cancers may undergo the developmental stages of benign proliferation, precancer and invasive cancer. Identification of biomarkers that are expressed throughout the developmental stages will facilitate detection, prevention and therapy of cancer. Piwil2, a member of AGO/PIWI family of proteins, has been suggested to be associated with tumor development. Here we reported that piwil2 can be detected by immunohistochemistry (IHC) in various stages of human cervical squamous cell carcinomas and adenocarcinomas. Interestingly, piwil2 was also detected in some metaplastic epithelial cells as well as histologically "normal" appearing tissues adjacent to malignant lesions. While all the premalignant and malignant lesions expressed varying levels of piwil2, p16(INK4a) (p16), a surrogate indicator of high-risk human papillomavirus (HR-HPV) infection, was detected in only 84.62% of the specimens. In Papanicolaou (Pap) test, piwil2 was also detected in atypical glandular cells (AGC), low-grade (LSIL) and high-grade squamous intraepithelial lesions (HSIL), whereas p16 was not always concomitantly detected in the same specimens. The results suggest that piwil2 might play important roles throughout the process of cervical cancer development and have the potential to be used as a complementary marker for p16(INK4a). It is worth further study to improve the sensitivity and specificity of current screening methods for cervical cancers.
American Journal of Translational Research 01/2010; 2(2):156-69.
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James J Liu, Rulong Shen,
Li Chen,
Yin Ye,
Gang He,
Keding Hua,
David Jarjoura,
Toru Nakano,
Ganju K Ramesh,
Charles L Shapiro,
Sanford H Barsky,
Jian-Xin Gao
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ABSTRACT: Piwil2, a member of AGO/PIWI family of proteins, has been reported to be expressed in precancerous stem cells (pCSCs), tumor cell lines and various types of human cancers. However, the significance of piwil2 expression in breast cancer has not been investigated. In this study, archival formalin-fixed, paraffin-embedded breast cancer specimens at various developmental stages were prepared as tissue microarrays (TMAs) and examined for the expressions of piwil2, estrogen receptor (ER), progesterone receptor (PR) and a cell proliferation marker Ki67 by immunohistochemical (IHC) staining and human epidermal growth factor receptor 2 (HER2) by fluorescence in situ hybridization (FISH). The correlation of piwil2 expression with ER, PR and Ki67 were analyzed statistically. The piwil2 was detected in all of breast cancer TMA cores. In contrast, ER, PR, HER2, and Ki67 were detected only in 66.1%, 54.5%, 36.0%, and 47% of the TMA cores, respectively. Piwil2 was expressed in cytoplasm (Cyt), nucleus (N) or both cytoplasm and nucleus (C-N). The N pattern was less observed in breast precancers, whereas all three patterns were observed in invasive and metastatic cancers. While the Cyt pattern was significantly correlated with ER expression (p = 0.002); N pattern was significantly correlated with Ki67 expression (p =0.001). ER and Ki67 expressions were reduced and increased, respectively, with the expression patterns being shifted from Cyt --> C-N --> N. In conclusion, piwil2 is expressed in various stages of breast cancers and has the potential to be used a novel biomarker.
International journal of clinical and experimental pathology 01/2010; 3(4):328-37. · 1.89 Impact Factor
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ABSTRACT: The role of aberrant methylation of fragile histidine triad (FHIT) promoters in the differentiated thyroid carcinoma (DTC) is not yet clear. Therefore, we investigated the association of the status of FHIT promoter methylation and FHIT protein expression with the clinicopathological progression of DTC, using PCR-based methylation assay and immunohistochemical technique. While no FHIT gene promoter methylation was observed in the matched non-cancerous epithelium (NCE) specimens, 24.6% of DTC samples demonstrated methylation in the FHIT promoter region. The protein expression of FHIT in NCE and DTC was 100.0% and 41.5% (P<0.01), respectively. There was a negative correlation between promoter methylation and protein expression of FHIT gene (P<0.05). Additionally, the methylation status appeared to be significantly associated with the pathological grade, tumor TNM stage, and lymph node metastasis (P<0.05), and FHIT proteins were weakly expressed in only about 20% of DTC with grade II pathological changes, TNM stage III/IV, or lymph node metastasis. Finally, the gender and tumor classification but not age marginally affected the promoter methylation and protein expression of FHIT. Our results suggest that methylation of the promoter region may play a key role in inactivation of FHIT - possibly leading to subsequent carcinogenesis and progression of DTC.
International journal of clinical and experimental pathology 01/2010; 3(5):482-91. · 1.89 Impact Factor
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Yin Ye,
De-Tao Yin,
Li Chen,
Quansheng Zhou, Rulong Shen,
Gang He,
Qingtao Yan,
Zhenyu Tong,
Andrew C Issekutz,
Charles L Shapiro,
Sanford H Barsky,
Haifan Lin,
Jian-Jian Li,
Jian-Xin Gao
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ABSTRACT: PIWIL2, a member of PIWI/AGO gene family, is expressed in the germline stem cells (GSCs) of testis for gametogenesis but not in adult somatic and stem cells. It has been implicated to play an important role in tumor development. We have previously reported that precancerous stem cells (pCSCs) constitutively express Piwil2 transcripts to promote their proliferation. Here we show that these transcripts de facto represent Piwil2-like (PL2L) proteins. We have identified several PL2L proteins including PL2L80, PL2L60, PL2L50 and PL2L40, using combined methods of Gene-Exon-Mapping Reverse Transcription Polymerase Chain Reaction (GEM RT-PCR), bioinformatics and a group of novel monoclonal antibodies. Among them, PL2L60 rather than Piwil2 and other PL2L proteins is predominantly expressed in various types of human and mouse tumor cells. It promotes tumor cell survival and proliferation in vitro through up-regulation of Stat3 and Bcl2 gene expressions, the cell cycle entry from G(0/1) into S-phase, and the nuclear expression of NF-κB, which contribute to the tumorigenicity of tumor cells in vivo. Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers. Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB. These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction. The identification of PL2L proteins provides a novel insight into the mechanisms of cancer development as well as a novel bridge linking cancer diagnostics and anticancer drug development.
PLoS ONE 01/2010; 5(10):e13406. · 4.09 Impact Factor
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Huey-Jen L Lin,
Tao Zuo,
Ching-Hung Lin,
Chieh Ti Kuo,
Sandya Liyanarachchi,
Shuying Sun, Rulong Shen,
Daniel E Deatherage,
Dustin Potter,
Lisa Asamoto,
Shili Lin,
Pearlly S Yan,
Ann-Lii Cheng,
Michael C Ostrowski,
Tim H-M Huang
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ABSTRACT: The interplay between histone modifications and promoter hypermethylation provides a causative explanation for epigenetic gene silencing in cancer. Less is known about the upstream initiators that direct this process. Here, we report that the Cystatin M (CST6) tumor suppressor gene is concurrently down-regulated with other loci in breast epithelial cells cocultured with cancer-associated fibroblasts (CAF). Promoter hypermethylation of CST6 is associated with aberrant AKT1 activation in epithelial cells, as well as the disabled INNP4B regulator resulting from the suppression by CAFs. Repressive chromatin, marked by trimethyl-H3K27 and dimethyl-H3K9, and de novo DNA methylation is established at the promoter. The findings suggest that microenvironmental stimuli are triggers in this epigenetic cascade, leading to the long-term silencing of CST6 in breast tumors. Our present findings implicate a causal mechanism defining how tumor stromal fibroblasts support neoplastic progression by manipulating the epigenome of mammary epithelial cells. The result also highlights the importance of direct cell-cell contact between epithelial cells and the surrounding fibroblasts that confer this epigenetic perturbation. Because this two-way interaction is anticipated, the described coculture system can be used to determine the effect of epithelial factors on fibroblasts in future studies.
Cancer Research 01/2009; 68(24):10257-66. · 7.86 Impact Factor
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ABSTRACT: An 89-year-old woman was seen for indigestion, light chest pain, and melanotic stools. Endoscopic examination revealed 2 submucosal gastric masses. A subtotal gastrectomy showed 2 submucosal masses in the stomach: one infiltrating through the muscularis propria into the serosa, the second one, a well-circumscribed submucosal nodule. Histologic examination showed large tumor cells infiltrating diffusely through the muscularis propria into the subserosa. On higher magnification, numerous signet ring cells were present against a myxoid stroma, in addition to large vacuolated epithelioid cells. There was no evidence of invasion, necrosis, nuclear pleomorphism, or mitotic activity. Initial diagnostic considerations based on the histology included signet ring cell carcinoma, malignant melanoma, and a myxoid mesenchymal tumor, including gastrointestinal stromal tumor. A panel of immunohistochemical stains showed diffuse strong positivity for S-100 protein and negative reaction for CD117, bcl-2, cytokeratin AE1/AE3, Melan-A, HMB45, smooth muscle antigen, and other differentiation markers. Electron microscopic examination revealed elongated, complex, and interdigitating cell processes covered by a thin layer of continuous basement membrane material characteristic of peripheral nerve sheath differentiation. The presentation of this tumor was significant in that it was multifocal and infiltrative, mimicking a malignant neoplasm. The extensive myxoid/signet ring cell change represents a heretofore-unreported histologic variant of gastric schwannoma.
Annals of Diagnostic Pathology 05/2008; 12(2):146-52. · 0.88 Impact Factor
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ABSTRACT: Tumor neo-vascularization is critical for tumor growth, invasion and metastasis, which has been considered to be mediated by a mechanism of angiogenesis. However, histopathological studies have suggested that tumor cells might be the progenitor for tumor vasculature. Recently, we have reported that the precancerous stem cells (pCSCs) representing the early stage of developing cancer stem cells (CSCs), have the potential for both benign and malignant differentiation. Therefore, we investigated whether pCSCs serve as progenitors for tumor vasculogenesis. Herein, we report that in the pCSC-derived tumors, most blood vessels were derived from pCSCs. Some pCSCs constitutively expressed vasculogenic receptor VEGFR-2, which can be up-regulated by hypoxia and angiogenesis-promoting cytokines, such as GM-CSF, Flt3 ligand, and IL-13. The pCSCs are much more potent in tumor vasculogenesis than the differentiated tumor monocytic cells (TMCs) from the same tumor, which had comparable or even higher capacity to produce some vascular growth factors, suggesting that the potent tumor vasculogenesis of pCSCs is associated with their intrinsic stem-like property. Consistently tumor vasculogenesis was also observed in human cancers such as cervical cancer and breast cancer and xenograft lymphoma. Our studies indicate that pCSCs can serve as tumor vasculogenic stem/progenitor cells (TVPCs), and may explain why anti-angiogenic cancer therapy trials are facing challenge.
PLoS ONE 02/2008; 3(2):e1652. · 4.09 Impact Factor
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ABSTRACT: We report a case of invasive micropapillary carcinoma of the sigmoid colon in a 72-year-old female with anemia and abdominal pain. Grossly, the tumor demonstrated a deeply invasive, ulcerated fungating mass. Microscopically, the carcinoma was predominantly composed of micropapillae with reversed cell polarity, abundant neutrophils, and surrounded by clear spaces. Multifocal lymphovascular invasion was present with extensive lymph node metastasis. Immunohistochemically, the carcinoma cells were positive for CDX2, CK20 and monoclonal carcinoembryonic antigen. They were negative for CK7. The stroma-facing surface of the micropapillae was positive for CD10 and villin, confirming the inside-out growth pattern characteristic of micropapillary carcinoma. Work-up for distance metastasis was negative. The patient was alive and well 1.5 years after sigmoidectomy and postoperative chemotherapy.
International journal of clinical and experimental pathology 02/2008; 1(5):457-60. · 1.89 Impact Factor
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ABSTRACT: Alterations in the global methylation of DNA and in specific regulatory genes are two epigenetic alterations found in cancer. However, the significance of epigenetic changes for diagnosis and/or prognosis of colorectal cancer have not been established, although it has been extensively investigated. Recently we have identified a new type of cancer cell called precancerous stem cells (pCSCs) and proposed that cancer may arise from a lengthy development process of tumor initiating cells (TICs) --> pCSCs --> cancer stem cells (CSCs) --> cancer, which is in parallel to histological changes of hyperplasia (TICs) --> precancer (pCSCs) --> carcinoma (CSCs/cancer cells), accompanied by clonal evolutionary epigenetic and genetic alterations. In this study, we investigated whether aberrant DNA methylation can be used as a biomarker for the differentiation between premalignant and malignant lesions in the colorectum. The profile of global DNA and estrogen receptor (ER)-alpha gene methylation during cancer development was determined by analysis of 5-methylcytosine (5-MeC) using immunohistochemical (IHC) staining, dot blot analysis or a quantitative gene methylation assay (QGMA). Herein we show that global DNA hypomethylation and ER-alpha gene hypermethylation are progressively enhanced from hyperplastic polyps (HPs) --> adenomatous polyps (APs) --> adenomatous carcinoma (AdCa). The aberrant methylation can be completely reversed in APs, but not in AdCa by a nonsteroidal anti-inflammatory drug (NSAID) celecoxib, which is a selective inhibitor of cyclooxygenase-2 (Cox-2), suggesting that the epigenetic alterations between colorectal precancer (AP) and cancer (AdCa) are fundamentally different in response to anti-cancer therapy. In normal colorectal mucosa, while global DNA methylation was not affected by aging, ER-alpha gene methylation was significantly increased with aging. However, this increase did not reach the level observed in colorectal APs. Taken together, reversibility of aberrant global DNA and ER-alpha gene methylation distinguishes colorectal precancer from cancer.
International journal of clinical and experimental pathology 02/2008; 2(1):21-33. · 1.89 Impact Factor
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Tao Zuo,
Lizhong Wang,
Carl Morrison,
Xing Chang,
Huiming Zhang,
Weiquan Li,
Yan Liu,
Yin Wang,
Xingluo Liu,
Michael W Y Chan, [......],
Richard Love,
Chang-Gong Liu,
Virginia Godfrey, Rulong Shen,
Tim H-M Huang,
Tianyu Yang,
Bae Keun Park,
Cun-Yu Wang,
Pan Zheng,
Yang Liu
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ABSTRACT: The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germline mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that female mice heterozygous for the "scurfin" mutation of the Foxp3 gene (Foxp3(sf/+)) developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and HER-2/ErbB2 was overexpressed. Foxp3 bound and repressed the HER-2/ErbB2 promoter. Deletion, functionally significant somatic mutations, and downregulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2/ErbB2 overexpression, regardless of the status of HER-2 amplification. Our data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.
Cell 07/2007; 129(7):1275-86. · 32.40 Impact Factor
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ABSTRACT: NK dendritic cells (DCs; NKDCs) appear to emerge as a distinct DC subset in humans and rodents, which have the functions of NK cells and DCs. However, the developmental relationship of NKDCs (CD11c(+)NK1.1(+)) to CD11c(+)NK1.1(-) DCs has not been addressed. Herein, we show that NKDCs exist exclusively in the compartment of CD11c(+)MHC II(-) cells in the steady state and express variable levels of DC subset markers, such as the IFN-producing killer DC marker B220, in a tissue-dependent manner. They can differentiate into NK1.1(-) DCs, which is accompanied by the up-regulation of MHC Class II molecules and down-regulation of NK1.1 upon adoptive transfer. However, NK cells (NK(+)CD11c(-)) did not differentiate into NK1.1(+)CD11c(+) cells upon adoptive transfer. Bone marrow-derived Ly6C(+) monocytes can be a potential progenitor of NKDCs, as some of them can differentiate into CD11c(+)NK1.1(+) as well as CD11c(+)NK1.1(-) cells in vivo. The steady-state NKDCs have a great capacity to lyse tumor cells but little capability to present antigens. Our studies suggest that NKDCs are an intermediate of developing DCs. These cells appear to bear the unique surface phenotype of CD11c(+)NK1.1(+)MHC II(-) and possess strong cytotoxic function yet show a poor ability to present antigen in the steady state. These findings suggest that NKDCs may play a critical role in linking innate and adaptive immunity.
Journal of Leukocyte Biology 07/2007; 81(6):1422-33. · 4.99 Impact Factor
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Li Chen, Rulong Shen,
Yin Ye,
Xin-An Pu,
Xingluo Liu,
Wenrui Duan,
Jing Wen,
Jason Zimmerer,
Ying Wang,
Yan Liu, [......],
Nyla A Heerema,
Danilo Perrotti,
Keiko Ozato,
Satomi Kuramochi-Miyagawa,
Toru Nakano,
Allen J Yates,
William E Carson,
Haifan Lin,
Sanford H Barsky,
Jian-Xin Gao
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ABSTRACT: Cancer stem cells (CSCs) have been identified in hematopoietic and solid tumors. However, their precursors-namely, precancerous stem cells (pCSCs) -have not been characterized. Here we experimentally define the pCSCs that have the potential for both benign and malignant differentiation, depending on environmental cues. While clonal pCSCs can develop into various types of tissue cells in immunocompetent mice without developing into cancer, they often develop, however, into leukemic or solid cancers composed of various types of cancer cells in immunodeficient mice. The progress of the pCSCs to cancers is associated with the up-regulation of c-kit and Sca-1, as well as with lineage markers. Mechanistically, the pCSCs are regulated by the PIWI/AGO family gene called piwil2. Our results provide clear evidence that a single clone of pCSCs has the potential for both benign and malignant differentiation, depending on the environmental cues. We anticipate pCSCs to be a novel target for the early detection, prevention, and therapy of cancers.
PLoS ONE 02/2007; 2(3):e293. · 4.09 Impact Factor
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ABSTRACT: A case of low-grade malignant perineurioma presenting as a mass in the thigh is described. The patient was a 76-year-old woman with an enlarging painful mass on her right lateral thigh over the past 2 months. Thorough clinical and radiological studies did not reveal any evidence of tumor elsewhere. The patient underwent fine needle aspiration of the mass, which revealed pleomorphic spindle cells in small clusters or dispersed as single cells within myxoid stroma, cytologically consistent with a high-grade sarcoma. At surgery, the tumor was found to be entirely confined within the muscle. Grossly, the tumor measured 6.5 cm in greatest diameter and showed a gray-white fleshy cut surface that was well circumscribed but unencapsulated. Histologic examination showed a highly cellular spindle cell proliferation embedded within myxoid stroma. The tumor cells showed mild to moderate nuclear pleomorphism with minimal mitotic activity. No evidence of hemorrhage or necrosis was noted. The tumor irregularly invaded the surrounding skeletal muscle. Immunohistochemical studies showed weak membranous positivity for epithelial membrane antigen and focal cytoplasmic positivity for CD34; stains for smooth muscle actin, cytokeratin AE1/AE3, desmin, CD56, H-caldesmon, calponin, and S-100 protein were negative. Electron microscopy showed cells with thin, elongated cytoplasmic processes extending along connective tissue in a parallel, onion-like arrangement and prominent subplasmalemmal pinocytotic activity. The marked pleomorphism displayed on fine needle aspiration observed in this case can lead to a mistaken diagnosis of high-grade sarcoma resulting in unnecessarily aggressive management.
Annals of Diagnostic Pathology 09/2005; 9(4):197-201. · 0.88 Impact Factor
