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Jinan, China

Bai Z.,Chinese Institute of Basic Medical Sciences | Tai Y.,90th Hospital of Jinan | Li W.,Kimmel Cancer Center | Zhen C.,Chinese Institute of Basic Medical Sciences | And 9 more authors.
Cancer Research | Year: 2013

Hepatic metastasis is responsible for the majority of colorectal cancer (CRC)-related mortalities. Although Gankyrin (PSMD10) has been implicated in cancer metastasis, its exact role and underlying mechanisms of CRC hepatic metastasis remain largely unknown. Herein, we showed that the expression of Gankyrin was higher in primary CRC with hepatic metastasis compared with CRC without metastasis. RNAi-mediated silencing of Gankyrin expression in highly metastatic human CRC cells impaired their migratory and metastatic capacity in vivo. Genome-wide transcriptome profiling revealed activation of the interleukin (IL)-8 signaling pathway by Gankyrin. Protein levels of IL-8 and cyclin D1 (CCND1), the two important molecules in the IL-8 pathway, were positively correlated with Gankyrin expression in human CRC specimens. Furthermore, genetic deletion of cyclin D1 showed its requirement in Gankyrin-mediated cell migration. Finally, administration of recombinant IL-8 rescued the migratory defect of CRC cells where Gankyrin expression was silenced. Together, our findings highlight the importance of Gankyrin in hepatic metastasis of CRC and point out its candidature as a potential prognostic marker and therapeutic target to improve the clinical management of metastatic CRC. © 2013 AACR. Source


Pan X.,Chinese Institute of Basic Medical Sciences | Zhou T.,Chinese Institute of Basic Medical Sciences | Tai Y.-H.,Chinese Peoples Liberation Army | Wang C.,Thomas Jefferson University | And 18 more authors.
Nature Medicine | Year: 2011

Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain-"containing protein-2 (CUEDC2), a ubiquitin-binding motif-"containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer. © 2011 Nature America, Inc. All rights reserved. Source


Gu W.,Shandong University | Gu W.,Thomas Jefferson University | Wang C.,Thomas Jefferson University | Li W.,Shandong University | And 12 more authors.
Cell Cycle | Year: 2013

CDK8 is either amplified or mutated in a variety of human cancers, and CDK8 functions as an oncoprotein in melanoma and colorectal cancers. Previously, we reported that loss or reduction of CDK8 results in aberrant fat accumulation in Drosophila and mammals, suggesting that CDK8 plays an important role in inhibiting lipogenesis. Epidemiological studies have identified obesity and overweight as the major risk factors of endometrial cancer, thus we examined whether CDK8 regulates endometrial cancer cell growth by using several endometrial cancer cell lines, including KLE, which express low levels of CDK8, as well as AN3 CA and HEC-1A cells, which have high levels of endogenous CDK8. We observed that ectopic expression of CDK8 in KLE cells inhibited cell proliferation and potently blocked tumor growth in an in vivo mouse model. In addition, gain of CDK8 in KLE cells blocked cell migration and invasion in transwell, wound healing and persistence of migratory directionality assays. Conversely, we observed the opposite effects in all of the aforementioned assays when CDK8 was depleted in AN3 CA cells. Similar to AN3 CA cells, depletion of CDK8 in HEC-1A cells strongly enhanced cell migration in transwell assays, while overexpression of CDK8 in HEC-1A cells blocked cell migration. Furthermore, gene profiling of KLE cells overexpressing CDK8 revealed genes whose protein products are involved in lipid metabolism, cell cycle and cell movement pathways. Finally, depletion of CDK8 increased the expression of lipogenic genes in endometrial cancer cells. Taken together, these results show a reverse correlation between CDK8 levels and several key features of the endometrial cancer cells, including cell proliferation, migration and invasion as well as tumor formation in vivo. Therefore, in contrast to the oncogenic effects of CDK8 in melanoma and colorectal cancers, our results suggest that CDK8 plays a tumor-suppressive role in endometrial cancers. © 2013 Landes Bioscience. Source


Liu Y.,Shandong University | Li W.,Shandong University | Li X.,Shandong University | Tai Y.,90th Hospital of Jinan | And 3 more authors.
Archives of Gynecology and Obstetrics | Year: 2014

Objective: This study aimed to determine the expression level of biglycan in different lesion properties of endometrium and to investigate the possible function and prognostic value of biglycan in endometrial cancer. Methods: Immunohistochemical staining (IHC) and quantitative realtime reverse transcription polymerase chain reaction (qRT-PCR) were used to determine the protein and mRNA levels of biglycan in human normal endometrium, atypical hyperplasia endometrium, and endometrial cancer tissue samples. The expression of biglycan in serum and peritoneal washings was detected by ELISA method. Then we analyzed the correlation of biglycan expression with clinicopathological parameters in endometrial cancer. Results: (1) Biglycan was overexpressed in endometrial cancer, especially in cancerous mesenchyme. Moreover, biglycan expression was significantly correlated with histopathological grade and FIGO stage of endometrial cancer; (2) Biglycan expression level in sera and peritoneal washings was significantly higher in endometrial cancer patients; otherwise, Serum expression correlated with clinicopathological parameters of endometrial cancer; (3) Higher level expression of biglycan in cancerous mesenchyme correlated with poor prognosis of endometrial cancer. Conclusions: Biglycan might play a role in the progression of human endometrial cancer and it might be a useful molecular marker for the prognosis of endometrial cancer. This research is an initial step towards biglycan as a potential prognosis marker in endometrial cancer. © 2013 Springer-Verlag Berlin Heidelberg. Source


Li W.,Shandong University | Li W.,Thomas Jefferson University | Tai Y.,90th Hospital of Jinan | Zhou J.,Thomas Jefferson University | And 13 more authors.
Cell Cycle | Year: 2012

The aberrantly increased lipogenesis is a universal metabolic feature of proliferating tumor cells. Although most normal cells acquire the bulk of their fatty acids from circulation, tumor cells synthesize more than 90% of required lipids de novo. The sterol regulatory element-binding protein 1 (SREBP1), encoded by SREBF1 gene, is a master regulator of lipogenic gene expression. SREBP1 and its target genes are overexpressed in a variety of cancers; however, the role of SREBP1 in endometrial cancer is largely unknown. We have screened a cohort of endometrial cancer (EC) specimen for their lipogenic gene expression and observed a significant increase of SREBP1 target gene expression in cancer cells compared with normal endometrium. By using immunohistochemical staining, we confirmed SREBP1 protein overexpression and demonstrated increased nuclear distribution of SREBP1 in EC. In addition, we found that knockdown of SREBP1 expression in EC cells suppressed cell growth, reduced colonigenic capacity and slowed tumor growth in vivo. Furthermore, we observed that knockdown of SREBP1 induced significant cell death in cultured EC cells. Taken together, our results show that SREBP1 is essential for EC cell growth both in vitro and in vivo, suggesting that SREBP1 activity may be a novel therapeutic target for endometrial cancers. © 2012 Landes Bioscience. Source

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