Hunan Key Laboratory of Nonresolving Inflammation and Cancer

Changsha, China

Hunan Key Laboratory of Nonresolving Inflammation and Cancer

Changsha, China
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Sun Y.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | Sun Y.,Central South University | Shen S.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | Shen S.,Central South University | And 12 more authors.
Molecular and Cellular Biochemistry | Year: 2014

The 5-year survival rate for colorectal cancer is approximately 55 % because of its invasion and metastasis. The epithelial-mesenchymal transition (EMT) is one of the well-defined processes during the invasion and distant metastasis of primary epithelial tumors. miR-429, a member of the miR-200 family of microRNAs, was previously shown to inhibit the expression of transcriptional repressors ZEB1/delta EF1 and SIP1/ZEB2, and regulate EMT. In this study, we showed that miR-429 was significantly downregulated in colorectal carcinoma (CRC) tissues and cell lines. We found that miR-429 inhibited the proliferation and growth of CRC cells in vitro and in vivo, suggesting that miR-429 could play a role in CRC tumorigenesis. We also showed that downregulation of miR-429 may contribute to carcinogenesis and the initiation of EMT of CRC by targeting Onecut2. Further researches indicated that miR-429 inhibited the cells migration and invasion and reversed TGF-β-induced EMT changes in SW620 and SW480 cells. miR-429 could reverse the change of EMT-related markers genes induced by TGF-β1, such as E-cadherin, CTNNA1, CTNNB1, TFN, CD44, MMP2, Vimentin, Slug, Snail, and ZEB2 by targeting Onecut2. Taken together, our data showed that transcript factor Onecut2 is involved in the EMT, migration and invasion of CRC cells; miR-429 inhibits the initiation of EMT and regulated expression of EMT-related markers by targeting Onecut2; and miR-429 or Onecut2 is the important therapy target for CRC. © 2014 The Author(s).


Chen Z.,Central South University | Liu S.,Central South University | Tian L.,Central South University | Wu M.,The Hunan Provincial Peoples Hospital | And 9 more authors.
Oncotarget | Year: 2015

miR-124 and miR-506 are reportedly down-regulated and associated with tumor progression in many cancers, but little is known about their intrinsic regulatory mechanisms in colorectal cancer (CRC). In this study, we found that the miR-124 and miR-506 levels were significantly lower in human CRC tissues than in controls, as indicated by qRT-PCR and in situ hybridization histochemistry. We also found that the overexpression of miR-124 or miR-506 inhibited tumor cell progression and increased sensitivity to chemotherapy in vitro. Increased miR-124 or miR-506 expression also inhibited tumor cell proliferation and invasion in vivo. Luciferase reporter assays and western blotting were used to determine the association between miR-124, miR-506 and their target genes, DNMTs. We further identified that miR-124 and miR-506 directly targeted DNMT3B and indirectly targeted DNMT1. The overexpression of miR-124 and miR-506 reduced global DNA methylation and restored the expression of E-cadherin, MGMT and P16. In conclusion, our data showed that miR-124 and miR-506 inhibit progression and increase sensitivity to chemotherapy by targeting DNMT3B and DNMT1 in CRC. These findings may provide novel avenues for the development of targeted therapies.


Wang W.,Central South University | Li X.,Central South University | Zhang W.,Central South University | Li W.,Central South University | And 10 more authors.
Cancer Letters | Year: 2014

Oxidored-nitro domain containing protein 1 (NOR1) is a putative tumor suppressor gene. In this study, NOR1 expression was detected in NPC tissues and non-cancerous nasopharyngeal epithelium. The data showed that NOR1 protein was decreased in NPC tissues. Lost expression NOR1 protein was associated with poor overall and event-free survival of NPC patients. Overexpression of NOR1 in NPC cells resulted in a significant morphological change and decreased expression of epithelial-to-mesenchymal transition (EMT) mediators (e.g., slug and vimentin), but induced cytokeratin 13 expression. A nude mouse metastasis assay revealed that overexpression of NOR1 decreased NPC tumor cells metastasis capacity in vivo. Knockdown of NOR1 expression in HeLa cells was sufficient to abrogate epithelial traits and to enhance cell migration and invasion. Concomitant inhibition of slug or vimentin alleviated induction of EMT, migration or invasion by NOR1 siRNA in HeLa cells in vitro. In conclusion, the data from the current study suggest, for the first time, that NOR1 plays an important role in NPC in ex vivo, in vitro, and in vivo. © 2014 Elsevier Ireland Ltd.


Luo Z.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | Luo Z.,Central South University | Dai Y.,Central South University | zhang L.,Central South University | And 15 more authors.
Carcinogenesis | Year: 2013

Dysregulation of microRNA (miRNA) biogenesis is implicated in cancer development and progression. Dicer and Drosha are established regulators of miRNA biogenesis. In this study, we used a miRNA array to evaluate the miRNA expression profiles in nasopharyngeal carcinoma (NPC) samples. The significance analysis of microarrays showed a global downregulation of miRNA expression in NPC samples compared with normal nasopharyngeal epithelial tissues. Notably, miR-18a, a member of the oncogenic miR-17-92 cluster, was upregulated in the NPC samples and ell lines. Clinical parameter studies showed that higher levels of miR-18a correlated with NPC advanced stage, lymph node metastasis, Epstein-Barr virus infection and a higher death rate from NPC, indicating oncogenic roles in NPC development. The expression levels of miR-18a and Dicer1 were inversely related in NPC tissues. Further studies demonstrated that miR-18a negatively regulated Dicer1 by binding to the 3' untranslated regions of Dicer1. In vitro and in vivo biological function assays showed that miR-18a promoted the growth, migration and invasion of NPC cells by regulating Dicer1 expression, which caused the global downregulation of miRNA expression levels including miR-200 family and miR-143. Furthermore, we found that the epithelial mesenchymal transition marker E-cadherin and the oncogene K-Ras were aberrantly expressed after miR-18a transduction, and these alterations were directly induced by downregulation of the miR-200 family and miR-143. Collectively, our findings indicate that miR-18a plays an oncogenic role in the development of NPC by widespread downregulation of the miRNome and could be a potential therapeutic target for NPC. © The Author 2012. Published by Oxford University Press.


Li N.,Central South University | Li N.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | Tang A.,Central South University | Tang A.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | And 14 more authors.
Molecular and Cellular Biochemistry | Year: 2013

Recent data strongly suggests the profound role of miRNAs in cancer progression. Here, we showed miR-126 expression was much lower in HCT116, SW620 and HT-29 colon cancer cells with highly metastatic potential and miR-126 downregulation was more frequent in colorectal cancers with metastasis. Restored miR-126 expression inhibited HT-29 cell growth, cell-cycle progression and invasion. Mechanically, microarray results combined with bioinformatic and experimental analysis demonstrated miR-126 exerted cancer suppressor role via inhibiting RhoA/ROCK signaling pathway. These results suggest miR-126 function as a potential tumor suppressor in colon cancer progression and miR-126/RhoA/ROCK may be a novel candidate for developing rational therapeutic strategies. © 2013 Springer Science+Business Media New York.


Zhou W.,Central South University | Li X.,Central South University | Li X.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | Liu F.,Central South University | And 4 more authors.
Acta Biochimica et Biophysica Sinica | Year: 2012

MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases. The miR-135a is considered to be oncogenic; however, the functions and mechanisms of miR-135a in colorectal cancer (CRC) are largely unknown. Thus, we investigated the functions and mechanisms of miR-135a, especially its relationship with the metastasis suppressor 1 (MTSS1) gene in CRC. The expression of miR-135a was determined by real-time polymerase chain reaction, while its effect on cell proliferation, migration, and invasion was determined by MTT, without and with matrigel, respectively. The expression of MTSS1 was detected by western blot analysis. It was found that miR-135a expression was higher in human CRC samples than in non-tumor control tissue. Using SW480 and SW620 CRC cell lines, increased proliferation was observed in response to miR-135a. We also demonstrated that miR-135a promoted mobility and invasion via transwell assay with and without Matrigel, respectively, of CRC cells. In contrast, inhibition of miR-135a reduced their proliferative and invasive capability. MTSS1 was identified as a candidate target gene of miR-135a by luciferase report assay. Western blot analysis showed that the expression of MTSS1 was regulated by miR-135a overexpression and knockdown. Similarly, miR-135a-mediated cell mobility and invasion were reduced after MTSS1 was knocked down by small interfering RNA. These data indicated that miR-135a promotes the growth and invasion of CRC cells, at least partially, through targeting MTSS1. © 2012 The Author.


Tang A.,Central South University | Tang A.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | Li N.,Central South University | Li N.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | And 16 more authors.
Carcinogenesis | Year: 2012

An association between carcinogenesis and inflammation has long been appreciated. Chemically induced colitis-associated cancer (CAC) is a classical mouse model for investigating 'inflammation- cancer link' in the intestine. Diverse mechanisms behind this non-resolving inflammation model have been reported before, most of them were emphasized on key cancer genes, cytokines, and signal transduction abnormality based on prior knowledge. In this study, we dynamically and globally dissect the alteration of key pathways in the development from colitis to colorectal cancer. Striking evidence from gene expression profiling, serum cytokines detection, and immunohistochemistry analysis all reveals that different key pathways [NF-κB, STAT3, p38 mitogen-activated protein kinase (MAPK), and Wnt/β-catenin signaling] and their target genes are hyperactive in different phases of the inflammation-cancer link. Nuclear factor-κB (NF-κB) and STAT3 signaling are hyperactive in the whole process, while p38 MAPK and Wnt/β-catenin signaling are only hyperactive in the beginning and ending, respectively. Through this unbiased system biological approach, we provide strong evidence that different key pathways are specifically involved in different phases, which bridge the gap between inflammation and cancer. © The Author 2012. Published by Oxford University Press. All rights reserved.


Ai F.,Central South University | Ai F.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | Zhang X.,Central South University | Zhang X.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer | And 16 more authors.
Oncotarget | Year: 2015

Emerging evidence has implicated microRNAs in regulating the production of multiple inflammatory mediators including cytokines and chemokines. We previously elucidated the dynamic activation of key signals that link colitis to colorectal cancer. In this study, we observed a sharp increase in the levels of matrix metalloproteinases (Mmps) that provided a basis for the inflammation-cancer link, and we questioned whether this was a consequence of the dysregulation of Mmp-specific microRNAs, at least partly. We assayed a panel of murine microRNAs that were predicted to target Mmps and found they were downregulated in the inflammation-cancer link. Furthermore, we demonstrated that three murine microRNAs, namely miR-128, -134, and -330, can target the three Mmps Mmp3, Mmp10, and Mmp13, respectively. We also found that the level of the microRNA-processing enzyme Dicer1 was decreased in the inflammation-cancer link. These microRNAs functioned as tumor suppressors in colon cancer cells, attenuating the proliferation, migration, and invasion potential of murine colon cancer cells as well as angiogenesis and the growth of tumors derived from these cells. Our results suggest that microRNAs modulate the production of key inflammatory mediators and that microRNA dysfunction may contribute to the nonresolving inflammation associated with cancer.


PubMed | Hunan Key Laboratory of Nonresolving Inflammation and Cancer
Type: Journal Article | Journal: Carcinogenesis | Year: 2013

Dysregulation of microRNA (miRNA) biogenesis is implicated in cancer development and progression. Dicer and Drosha are established regulators of miRNA biogenesis. In this study, we used a miRNA array to evaluate the miRNA expression profiles in nasopharyngeal carcinoma (NPC) samples. The significance analysis of microarrays showed a global downregulation of miRNA expression in NPC samples compared with normal nasopharyngeal epithelial tissues. Notably, miR-18a, a member of the oncogenic miR-17-92 cluster, was upregulated in the NPC samples and cell lines. Clinical parameter studies showed that higher levels of miR-18a correlated with NPC advanced stage, lymph node metastasis, Epstein-Barr virus infection and a higher death rate from NPC, indicating oncogenic roles in NPC development. The expression levels of miR-18a and Dicer1 were inversely related in NPC tissues. Further studies demonstrated that miR-18a negatively regulated Dicer1 by binding to the 3 untranslated regions of Dicer1. In vitro and in vivo biological function assays showed that miR-18a promoted the growth, migration and invasion of NPC cells by regulating Dicer1 expression, which caused the global downregulation of miRNA expression levels including miR-200 family and miR-143. Furthermore, we found that the epithelial mesenchymal transition marker E-cadherin and the oncogene K-Ras were aberrantly expressed after miR-18a transduction, and these alterations were directly induced by downregulation of the miR-200 family and miR-143. Collectively, our findings indicate that miR-18a plays an oncogenic role in the development of NPC by widespread downregulation of the miRNome and could be a potential therapeutic target for NPC.


PubMed | Hunan Key Laboratory of Nonresolving Inflammation and Cancer and Central South University
Type: Journal Article | Journal: Oncotarget | Year: 2015

Emerging evidence has implicated microRNAs in regulating the production of multiple inflammatory mediators including cytokines and chemokines. We previously elucidated the dynamic activation of key signals that link colitis to colorectal cancer. In this study, we observed a sharp increase in the levels of matrix metalloproteinases (Mmps) that provided a basis for the inflammation-cancer link, and we questioned whether this was a consequence of the dysregulation of Mmp-specific microRNAs, at least partly. We assayed a panel of murine microRNAs that were predicted to target Mmps and found they were downregulated in the inflammation-cancer link. Furthermore, we demonstrated that three murine microRNAs, namely miR-128, -134, and -330, can target the three Mmps Mmp3, Mmp10, and Mmp13, respectively. We also found that the level of the microRNA-processing enzyme Dicer1 was decreased in the inflammation-cancer link. These microRNAs functioned as tumor suppressors in colon cancer cells, attenuating the proliferation, migration, and invasion potential of murine colon cancer cells as well as angiogenesis and the growth of tumors derived from these cells. Our results suggest that microRNAs modulate the production of key inflammatory mediators and that microRNA dysfunction may contribute to the non-resolving inflammation associated with cancer.

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