Time filter

Source Type

Xu L.,South China University of Technology | Tong X.,General Hospital Cancer Center Key Laboratory | Tong X.,CAS Institute of Process Engineering | Zhang S.,General Hospital Cancer Center Key Laboratory | And 11 more authors.
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016

Hepatocellular carcinoma (HCC) is the third leading cause of death in cancer patients worldwide. Understanding the molecular pathogenesis of HCC recurrence and chemoresistance is key to improving patients' prognosis. In this study, we report that downregulation of ASPP2, a member of the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein (ASPP) family, bestowed HCC cells with stem-like properties and resistance to chemotherapy, including the expansion of side population fractions, formation of hepatospheroids, expression of stem cell-associated genes, loss of chemosensitivity, and increased tumorigenicity in immunodeficient mice. An expression profiling assay revealed that ASPP2 specifically repressed focal adhesion kinase (FAK)/Src/extracellular signal regulated kinase (ERK) signaling. ASPP2 does this by physically interacting with C-terminal Src kinase (CSK) and stimulating its kinase activity, which eventually leads to activator protein 1 (AP1)-mediated downregulation of Snail expression. In addition, pharmacologic inhibition of Src attenuated the effects of ASPP2 deficiency. Our findings present functional and mechanistic insight into the critical role of ASPP2 in the inhibition of HCC stemness and drug resistance and may provide a new strategy for therapeutic combinations to treat HCC.


Li W.,International Medical University | Li W.,State Key Laboratory of Antibody Medicine and Targeting Therapy | Wei H.,International Medical University | Li H.,International Medical University | And 5 more authors.
Nanomedicine | Year: 2014

Immunotherapy is a promising option for cancer treatment that might cure cancer with fewer side effects by primarily activating the host's immune system. However, the effect of traditional immunotherapy is modest, frequently due to tumor escape and resistance of multiple mechanisms. Pharmaceutical nanotechnology, which is also called cancer nanotechnology or nanomedicine, has provided a practical solution to solve the limitations of traditional immunotherapy. This article reviews the latest developments in immunotherapy and nanomedicine, and illustrates how nanocarriers (including micelles, liposomes, polymer-drug conjugates, solid lipid nanoparticles and biodegradable nanoparticles) could be used for the cellular transfer of immune effectors for active and passive nanoimmunotherapy. The fine engineering of nanocarriers based on the unique features of the tumor microenvironment and extra-/intra-cellular conditions of tumor cells can greatly tip the triangle immunobalance among host, tumor and nanoparticulates in favor of antitumor responses, which shows a promising prospect for nanoimmunotherapy. © 2014 Future Medicine Ltd.


PubMed | University of Minnesota, Chinese PLA General Hospital, The 150th Hospital of Chinese PLA, State Key Laboratory of Antibody Medicine and Targeting Therapy and International Medical University
Type: | Journal: Oncotarget | Year: 2016

Radiotherapy for esophageal squamous cell carcinoma (ESCC) patients is limited by resistance to ionizing radiation (IR). However, the roles and mechanisms of microRNAs in radioresistance are obscure. Here, we investigated that microRNA-205 (miR-205) was upregulated in radioresistant (RR) ESCC cells compared with the parental cells. Overexpression of miR-205 promoted colony survival post-IR, whereas depletion of miR-205 sensitized ESCC cells to IR in vitro and in vivo. Further, we demonstrated that miR-205 promoted radioresistance by enhancing DNA repair, inhibiting apoptosis and activating epithelial-mesenchymal transition (EMT). Mechanistically, miR-205, upregulated post-IR, was demonstrated to be activated by Sp1 in parallel with its host gene, miR-205HG, both of which showed a perfect correlation. We also identified and validated phosphatase and tensin homolog (PTEN), as a target of miR-205 that promoted radioresistance via PI3K/AKT pathway. Lastly, increased miR-205 expression was closely associated with decreased PTEN expression in ESCC tissues and miR-205 expression predicted poor prognosis in patients with ESCC. Taken together, these findings identify miR-205 as a critical determinant of radioresistance and a biomarker of prognosis. The Sp1-mediated transcriptional activation of miR-205 promotes radioresistance through PTEN via PI3K/AKT pathway in ESCC. Inhibition of miR-205 expression may be a new strategy for radiotherapy in ESCC.


Tong X.,International Medical University | Tong X.,Chinese PLA General Hospital | Tong X.,Shandong University | Li L.,Chinese University of Hong Kong | And 22 more authors.
Oncotarget | Year: 2014

SOX10 was identified as a methylated gene in our previous cancer methylome study. Here we further analyzed its epigenetic inactivation, biological functions and related cell signaling in digestive cancers (colorectal, gastric and esophageal cancers) in detail. SOX10 expression was decreased in multiple digestive cancer cell lines as well as primary tumors due to its promoter methylation. Pharmacologic or genetic demethylation reversed SOX10 silencing. Ectopic expression of SOX10 in SOX10-deficient cancer cells inhibits their proliferation, tumorigenicity, and metastatic potentials in vitro and in vivo. SOX10 also suppressed the epithelial to mesenchymal transition (EMT) and stemness properties of digestive tumor cells. Mechanistically, SOX10 competes with TCF4 to bind β-catenin and transrepresses its downstream target genes via its own DNA-binding property. SOX10 mutations that disrupt the SOX10-β-catenin interaction partially prevented tumor suppression. SOX10 is thus a commonly inactivated tumor suppressor that antagonizes Wnt/β-catenin signaling in cancer cells from different digestive tissues.


Xu L.,South China University of Technology | Tong X.,General Hospital Cancer Center Key Laboratory | Tong X.,CAS Institute of Process Engineering | Zhang S.,General Hospital Cancer Center Key Laboratory | And 13 more authors.
Tumor Biology | Year: 2016

Hepatocellular carcinoma (HCC) is the third leading cause of death in cancer patients worldwide. Understanding the molecular pathogenesis of HCC recurrence and chemoresistance is key to improving patients’ prognosis. In this study, we report that downregulation of ASPP2, a member of the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein (ASPP) family, bestowed HCC cells with stem-like properties and resistance to chemotherapy, including the expansion of side population fractions, formation of hepatospheroids, expression of stem cell-associated genes, loss of chemosensitivity, and increased tumorigenicity in immunodeficient mice. An expression profiling assay revealed that ASPP2 specifically repressed focal adhesion kinase (FAK)/Src/extracellular signal regulated kinase (ERK) signaling. ASPP2 does this by physically interacting with C-terminal Src kinase (CSK) and stimulating its kinase activity, which eventually leads to activator protein 1 (AP1)-mediated downregulation of Snail expression. In addition, pharmacologic inhibition of Src attenuated the effects of ASPP2 deficiency. Our findings present functional and mechanistic insight into the critical role of ASPP2 in the inhibition of HCC stemness and drug resistance and may provide a new strategy for therapeutic combinations to treat HCC. © 2016 International Society of Oncology and BioMarkers (ISOBM)


PubMed | State Key Laboratory of Antibody Medicine and Targeting Therapy, South China University of Technology and General Hospital Cancer Center Key Laboratory
Type: Journal Article | Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016

Hepatocellular carcinoma (HCC) is the third leading cause of death in cancer patients worldwide. Understanding the molecular pathogenesis of HCC recurrence and chemoresistance is key to improving patients prognosis. In this study, we report that downregulation of ASPP2, a member of the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein (ASPP) family, bestowed HCC cells with stem-like properties and resistance to chemotherapy, including the expansion of side population fractions, formation of hepatospheroids, expression of stem cell-associated genes, loss of chemosensitivity, and increased tumorigenicity in immunodeficient mice. An expression profiling assay revealed that ASPP2 specifically repressed focal adhesion kinase (FAK)/Src/extracellular signal regulated kinase (ERK) signaling. ASPP2 does this by physically interacting with C-terminal Src kinase (CSK) and stimulating its kinase activity, which eventually leads to activator protein 1 (AP1)-mediated downregulation of Snail expression. In addition, pharmacologic inhibition of Src attenuated the effects of ASPP2 deficiency. Our findings present functional and mechanistic insight into the critical role of ASPP2 in the inhibition of HCC stemness and drug resistance and may provide a new strategy for therapeutic combinations to treat HCC.


Zhao L.,International Medical University | Zhao L.,General Hospital Cancer Center | Zhao L.,State Key Laboratory of Antibody Medicine and Targeting Therapy | Tong Q.,International Medical University | And 25 more authors.
Blood | Year: 2013

Although monoclonal antibodies, including CD20 antibody rituximab, are standard therapeutics for several cancers, their efficacy remains variable and often modest. There is an urgent need to enhance the efficacy of the current generation of anticancer antibodies. Flt3 ligand, a soluble protein, has the ability to induce substantial expansion of dendritic cells (DCs). In this study, we constructed a bispecific immunoglobulin G-like bispecific fusion protein (BiFP) targeting both CD20 and Flt3 (CD20-Flex) by using CrossMab technology. We found that the BiFP exhibited stabilities that were comparable with the parental antibody rituximab and were able to bind to both targets with unaltered binding affinity.Notably, our data indicatedthatCD20-Flex BiFPcould not only eliminate lymphoma temporarily but also potentiate tumor-specific T-cell immunity,which affords a long-lasting protection fromtumor recurrence. The results showed that the expansion and infiltration of DCs into tumor tissues by CD20-Flex BiFP could be an effectiveway to generate protective immune responses against cancer, suggesting that the CD20-Flex BiFP could be a promising therapeutic agent against B-cell lymphomas. © 2013 by The American Society of Hematology.


Li G.,South China University of Technology | Zhao L.,South China University of Technology | Li W.,International Medical University | Li W.,Liaocheng University | And 19 more authors.
Oncotarget | Year: 2014

Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.


Zhao L.,International Medical University | Zhao L.,General Hospital Cancer Center | Zhao L.,State Key Laboratory of Antibody Medicine and Targeting Therapy | Xie F.,General Hospital Cancer Center | And 31 more authors.
mAbs | Year: 2014

Although rituximab has revolutionized the treatment of hematological malignancies, the acquired resistance is one of the prime obstacles for cancer treatment, and development of novel CD20-targeting antibodies with potent anti-tumor activities and specificities is urgently needed. Emerging evidence has indicated that lysosomes can be considered as an "Achilles heel" for cancer cells, and might serve as an effective way to kill resistant cancer cells. HLA-DR antibody L243 has been recently reported to elicit potent lysosome-mediated cell death in lymphoma and leukemia cells, suggesting that HLA-DR could be used as a potential target against lymphoma. In this study, we generated a bispecific immunoglobulin G-like antibody targeting both CD20 and HLA-DR (CD20-243 CrossMab) through CrossMab technology. We found that the CrossMab could induce remarkably high levels of complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and anti-proliferative activity. Notably, although HLA-DR is expressed on normal and malignant cells, the CrossMab exhibited highly anti-tumor specificity, showing efficient eradication of hematological malignancies both in vitro and in vivo. Our data indicated that combined targeting of CD20 and HLA-DR could be an effective approach against malignancies, suggesting that CD20-243 CrossMab would be a promising therapeutic agent against lymphoma. © 2014 Landes Bioscience.

Loading State Key Laboratory of Antibody Medicine and Targeting Therapy collaborators
Loading State Key Laboratory of Antibody Medicine and Targeting Therapy collaborators