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Featured researches published by Shujun Fan.


Cell Death and Disease | 2014

Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment

Jun Mao; Shujun Fan; Wei Ma; P Fan; Bo Wang; Jian Zhang; Huan Wang; B Tang; Q Zhang; Xiaotang Yu; Lianhui Wang; Bo Song; Lianhong Li

The Wnt1 protein, a secreted ligand that activates Wnt signaling pathways, contributes to the self-renewal of cancer stem cells (CSCs) and thus may be a major determinant of tumor progression and chemoresistance. In a series of gastric cancer specimens, we found strong correlations among Wnt1 expression, CD44 expression, and the grade of gastric cancer. Stable overexpression of Wnt1 increased AGS gastric cancer cells’ proliferation rate and spheroids formation, which expressed CSC surface markers Oct4 and CD44. Subcutaneous injection of nude mice with Wnt1-overexpressing AGS cells resulted in larger tumors than injection of control AGS cells. Salinomycin, an antitumor agent, significantly reduced the volume of tumor caused by Wnt1-overexpressing AGS cells in vivo. This is achieved by inhibiting the proliferation of CD44+Oct4+ CSC subpopulation, at least partly through the suppression of Wnt1 and β-catenin expression. Taken together, activation of Wnt1 signaling accelerates the proliferation of gastric CSCs, whereas salinomycin acts to inhibit gastric tumor growth by suppressing Wnt signaling in CSCs. These results suggest that Wnt signaling might have a critical role in the self-renewal of gastric CSCs, and salinomycin targeting Wnt signaling may have important clinical applications in gastric cancer therapy.


Stem Cell Research & Therapy | 2013

Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway

Panhong Fan; Shujun Fan; Huan Wang; Jun Mao; Yu Shi; Mohammed Mohammed Ibrahim; Wei Ma; Xiaotang Yu; Zhenhuan Hou; Bo Wang; Lianhong Li

IntroductionThe existence of breast cancer stem-like cells (BCSCs) has profound implications for cancer prevention. Genistein, a predominant isoflavone found in soy products, has multiple robust anti-tumor effects in various cancers, especially in the breast and prostate cancer. In this study, we aimed to evaluate genistein inhibition of BCSCs and its potential mechanism by culturing MCF-7 breast cancer cells and implanting these cells into nude mice.MethodsCell counting, colony formation and cell apoptosis analysis were used to evaluate the effect of genistein on breast cancer cells’ growth, proliferation and apoptosis. We then used mammosphere formation assay and CD44CD24 staining to evaluate the effect of genistein on BCSCs in vitro. A nude mice xenograft model was employed to determine whether genistein could target BCSCs in vivo, as assessed by real-time polymerase chain reaction (PCR) and immunohistochemical staining. The potential mechanism was investigated utilizing real-time PCR, western blotting analysis and immunohistochemical staining.ResultsGenistein inhibited the MCF-7 breast cancer cells’ growth and proliferation and promoted apoptosis. Both in vitro and in vivo genistein decreased breast cancer stem cells, and inhibited breast cancer stem-like cells through down-regulation of the Hedgehog-Gli1 Signaling Pathway.ConclusionsWe demonstrated for the first time that genistein inhibits BCSCs by down-regulating Hedgehog-Gli1 signaling pathway. These findings provide support and rationale for investigating the clinical application of genistein in treating breast cancer, and specifically by targeting breast cancer stem cells.


The International Journal of Biochemistry & Cell Biology | 2013

ShRNA targeting Notch1 sensitizes breast cancer stem cell to paclitaxel

Jun Mao; Bo Song; Yu Shi; Bo Wang; Shujun Fan; Xiaotang Yu; Jianwu Tang; Lianhong Li

Breast cancer is currently the most lethal gynecologic malignancy in many countries, and paclitaxel is a cornerstone in the treatment of this malignancy. Unfortunately, the efficacy of paclitaxel is limited due to the development of drug resistance. Evidence has suggested that cancer stem cells (CSCs) are involved in resistance to various forms of therapies, including chemotherapy. However, the interaction between paclitaxel resistance and CSCs and its underlying mechanisms have not been previously explored. In this study, we confirmed that paclitaxel enriched breast CSCs (CD44+/CD24-) in a dose-dependent manner in MCF-7 human breast cancer cell line. We then demonstrated that Notch1 was overexpressed in breast CSCs isolated from paclitaxel-treated MCF-7 cells compared to non-CSCs. The short hairpin RNA (shRNA) mediated knock-down of Notch1 inhibited MCF-7 cell proliferation and induced cell apoptosis. The anti-apoptosis protein NF-κB was decreased significantly when treated with shRNA-Notch1, and this effect was sharply improved by combination with paclitaxel. Paclitaxel decreased CD44+/CD24- cell population in MCF-7 cells and reduced the size and number of primary mammospheres after down-regulating the Notch1. Furthermore, shRNA-Notch1 inhibited the growth of tumor xenografts in nude mice noticeably. RT-PCR and Western blotting analysis showed that the expressions of ALDH1, NICD, Hes-1 and the drug transporter ABCG2 were decreased both in vitro and in vivo. These results suggest that Notch1 might play a critical role in the resistance to paclitaxel, and targeting Notch1 may have important clinical applications in cancer therapy.


Chemico-Biological Interactions | 2015

Salinomycin exerts anticancer effects on human breast carcinoma MCF-7 cancer stem cells via modulation of Hedgehog signaling

Ying Lu; Wei Ma; Jun Mao; Xiaotang Yu; Zhenhuan Hou; Shujun Fan; Bo Song; Huan Wang; Jiazhi Li; Le Kang; Pixu Liu; Quentin Liu; Lianhong Li

Breast cancer tissue contains a small population of cells that have the ability to self-renew, these cells are known as breast cancer stem cells (BCSCs). The Hedgehog signal transduction pathway plays a central role in stem cell development, its aberrant activation has been shown to contribute to the development of breast cancer, making this pathway an attractive therapeutic target. Salinomycin (Sal) is a novel identified cancer stem cells (CSCs) killer, however, the molecular basis for its anticancer effects is not yet clear. In the current study, Sals ability to modulate the activity of key elements in the Hedgehog pathway was examined in the human breast cancer cell line MCF-7, as well as in a subpopulation of cancer stem cells identified within this cancer cell line. We show here that Sal inhibits proliferation, invasion, and migration while also inducing apoptosis in MCF-7 cells. Interestingly, in a subpopulation of MCF-7 cells with the CD44(+)/CD24(-) markers and high ALDH1 levels indicative of BCSCs, modulators of Hedgehog signaling Smo and Gli1 were significantly down-regulated upon treatment with Sal. These results demonstrate that Sal also inhibits proliferation and induces apoptosis of BCSCs, further establishing it as therapeutically relevant in the context of breast cancers and also indicating that modulation of Hedgehog signaling is one potential mechanism by which it exerts these anticancer effects.


Biomedicine & Pharmacotherapy | 2016

miR-221/222 enhance the tumorigenicity of human breast cancer stem cells via modulation of PTEN/Akt pathway

Bailong Li; Ying Lu; Honghai Wang; Xiaocui Han; Jun Mao; Jiazhi Li; Lihui Yu; Bo Wang; Shujun Fan; Xiaotang Yu; Bo Song

BACKGROUND The miR-221/222 cluster has been discovered to function as oncogene in human malignancies including breast cancer. However, the role of miR-221/222 in the self-renewal of breast cancer stem cells (BCSCs) is not fully understood. In this study, we examined the impact and mechanism of miR-221/222 on the breast cancer cell viability, migration and invasion, and propagation of BCSCs. METHODS Human breast cancer cell line MCF-7 was transfected with miR-221/222 mimics or inhibitors to overexpress or knock down miR-221/222 respectively using Lipofactamine 2000. The biological effects of miR-221 and miR-222 were then assessed by cell proliferation assay, colony formation assay and transwell chamber assays. CD44/CD24 staining and mammosphere formation assay were performed to evaluate the ability of BCSCs self-renewal. Potential target gene phosphatase and tensin homolog (PTEN) and its downstream effector, phosphorylated Akt (p-Akt) were identified by Western blot and qRT-PCR methods. RESULTS PTEN, a tumor suppressor gene, was confirmed as a target of miR-221/222 in breast cancer cell line MCF-7. Downregulation of PTEN by miR-221/222 increased the phosphorylation of Akt. Enforced expression of miR-221/222 promoted breast cancer cell proliferation, migration and invasion via targeting PTEN/Akt pathway. Importantly, ectopic expression of miR-221/222 enriched the proportion of CD44(+)/CD24(-) BCSCs and improved the mammosphere formation capacity through targeting PTEN/Akt pathway. Blocking the endogenous miR-221/222 restored PTEN expression and subsequently decreased Akt phosphorylation, and thereby reversed this phenotype. CONCLUSIONS Our results suggested that miR-221/222 enhance breast cancer growth, migration and invasion, meanwhile propagate the self-renewal of BCSCs. This is achieved possibly through targeting PTEN/Akt pathway. miR-221/222 might be a novel therapeutic candidate for human breast cancer.


Chemico-Biological Interactions | 2016

Salinomycin suppresses TGF-β1-induced epithelial-to-mesenchymal transition in MCF-7 human breast cancer cells.

Chunying Zhang; Ying Lu; Qing Li; Jun Mao; Zhenhuan Hou; Xiaotang Yu; Shujun Fan; Jiazhi Li; Tong Gao; Bing Yan; Bo Wang; Bo Song; Lianhong Li

Epithelial-to-mesenchymal transition (EMT) is the major cause of breast cancer to initiate invasion and metastasis. Salinomycin (Sal) has been found as an effective chemical compound to kill breast cancer stem cells. However, the effect of Sal on invasion and metastasis of breast cancer is unclear. In the present study, we showed that Sal reversed transforming growth factor-β1 (TGF-β1) induced invasion and metastasis accompanied with down-regulation of MMP-2 by experiments on human breast cancer cell line MCF-7. Sal was able to inhibit TGF-β1-induced EMT phenotypic transition and the activation of key signaling molecules involved in Smad (p-Smad2/3,Snail1) and non-Smad (β-catenin, p-p38 MAPK) signals which cooperatively regulate the induction of EMT. Importantly, in a series of breast cancer specimens, we found strong correlation among E-cadherin expression, β-catenin expression, and the lymph node metastatic potential of breast cancer. Our research suggests that Sal is promised to be a chemotherapeutic drug by suppressing the metastasis of breast cancer.


Biomedicine & Pharmacotherapy | 2014

Inhibition of annexin A7 gene and protein induces the apotosis and decreases the invasion, migration of the hepatocarcinoma cell line.

Yuhong Huang; Qing Wang; Yue Du; Lulu Bai; Fen Jin; Jun Zhang; Shujun Fan; Huaxin Wang; Lin Song; Yue Gao; Xianyan Wang; Jianwu Tang

Our previous studies have shown that annexin A7 (ANXA7) gives different expressions in the mouse hepatocarcinoma cell lines with low or high lymphatic metastatic potential in both gene and protein levels. In this study, whether by using RNA interference (RNAi) technique downregulating ANXA7 in the gene level or by using antibody against ANXA7 in the protein level, the depressed expression of ANXA7 could induce apotosis and decrease the invasion, migration capacities of the Hca-P cell, a hepatocarcinoma cell line with low lymphatic metastatic potential in vitro. The results indicate that ANXA7 is an important factor in tumors with the lymphatic metastasis.


Stem Cell Research & Therapy | 2016

microRNA -140-5p inhibits colorectal cancer invasion and metastasis by targeting ADAMTS5 and IGFBP5

Lihui Yu; Ying Lu; Xiaocui Han; Wenyue Zhao; Jiazhi Li; Jun Mao; Bo Wang; Jie Shen; Shujun Fan; Lu Wang; Mei Wang; Lianhong Li; Jianwu Tang; Bo Song

BackgroundColorectal cancer (CRC) is one of the most common malignancies in the world. microRNA-140-5p (miR-140) has been shown to be involved in cartilage development and osteoarthritis (OA) pathogenesis. Some contradictions still exist concerning the role of miR-140 in tumor progression and metastasis, and the underlying mechanism is uncertain.MethodsImmunohistochemistry was performed to determine the expressions of ADAMTS5 and IGFBP5 in CRC tissues. Human CRC cell lines HCT116 and RKO were transfected with miR-140 mimic, inhibitor, or small interfering RNA (siRNA) against ADAMTS5 or IGFBP5, respectively, using oligofectamine or lipofectamine 2000. Scratch-wound assay and transwell migration and invasion assays were used to evaluate the effects of miR-140 on the capabilities of migration and invasion. The levels of miR-140 and ADAMTS5 and IGFBP5 mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to examine the expression of ADAMTS5 and IGFBP5 proteins.ResultsmiR-140 was significantly reduced, whereas ADAMTS5 and IGFBP5 were upregulated, in the human CRC tissues compared to the corresponding normal colorectal mucosa. miR-140 downregulation and ADAMTS5 or IGFBP5 overexpression were associated with the advanced TNM stage and distant metastasis of CRC. There was a reverse correlation between miR-140 levels and ADAMTS5 and IGFBP5 expression in CRC tissues. ADAMTS5 and IGFBP5 were downregulated by miR-140 at both the protein and mRNA levels in the CRC cell lines. The gain-of- and loss-of-function studies showed that miR-140 inhibited CRC cell migratory and invasive capacities at least partially via downregulating the expression of ADAMTS5 and IGFBP5.ConclusionsThese findings suggest that miR-140 suppresses CRC progression and metastasis, possibly through downregulating ADAMTS5 and IGFBP5. miR-140 might be a potential therapeutic candidate for the treatment of CRC.


Biomedicine & Pharmacotherapy | 2015

Down-regulated expression of Annexin A7 induces apoptosis in mouse hepatocarcinoma cell line by the intrinsic mitochondrial pathway

Yuhong Huang; Yue Du; Xin Zhang; Lulu Bai; Mohmmed Mibrahim; Jun Zhang; Yuanyi Wei; Cong Li; Shujun Fan; Huaxin Wang; Zhiying Zhao; Jianwu Tang

Our previous studies have shown that decreased expression of Annexin A7 elevates apoptosis in Hca-P cells, a hepatocarcinoma cell line with lymphatic metastatic potential. In this study, RNA interference technique was used to down-regulate the expression of Annexin A7, and unmanipulated Hca-P cells and transfected nonspecific-sequence Hca-P cells as control. The down-regulation of Annexin A7 declined the cell viability after cisplatin exposure. And the reduced expression of Annexin A7 decreased the expression of Bcl2, increased the expression of Cytochrome-C in the cytoplasme, and then improved the expression of Caspase-3. However there was no significant effect on the expression of Bax, Caspase-12, Fas, FasL and Caspase-8. The results indicate that the decreased expression of Annexin A7 could inhibit the proliferation, and increase the apoptosis of Hca-P cells by affecting the expression of the apoptosis associated proteins by the mitochondrial pathway.


Molecular therapy. Nucleic acids | 2018

MicroRNA-140 Inhibits the Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer

Jiazhi Li; Kun Zou; Lihui Yu; Wenyue Zhao; Ying Lu; Jun Mao; Bo Wang; Lu Wang; Shujun Fan; Bo Song; Lianhong Li

MicroRNA-140, a cartilage-specific microRNA, has recently been implicated in the cancer progression. However, the comprehensive role of miR-140 in the invasion and metastasis of colorectal cancer (CRC) is still not fully understood. In this study, we confirmed that miR-140 downregulates SMAD family member 3 (Smad3), which is a key downstream effector of the TGF-β signaling pathway, at the translational level in the CRC cell lines. Ectopic expression of miR-140 inhibits the process of epithelial-mesenchymal transition (EMT), at least partially through targeting Smad3, and induces the suppression of migratory and invasive capacities of CRC cells in vitro. miR-140 also attenuates CRC cell proliferation possibly via downregulating Samd3. Furthermore, overexpression of miR-140 inhibits the tumor formation and metastasis of CRC in vivo, and silenced Smad3 has the similar effect. Additionally, miR-140 expression is decreased in the clinical primary CRC specimens and appears as a progressive reduction in the metastatic specimens, whereas Smad3 is overexpressed in the CRC samples. Taken together, our findings suggest that miR-140 might be a key suppressor of CRC progression and metastasis through inhibiting EMT process by targeting Smad3. miR-140 may represent a novel candidate for CRC treatment.

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Jun Mao

Dalian Medical University

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Lianhong Li

Dalian Medical University

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Bo Wang

Dalian Medical University

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Xiaotang Yu

Dalian Medical University

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Bo Song

Dalian Medical University

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Ying Lu

Dalian Medical University

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Jiazhi Li

Dalian Medical University

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Wei Ma

Dalian Medical University

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Huan Wang

Dalian Medical University

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Jianwu Tang

Dalian Medical University

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