Shun Li

Publications (4)12.4 Total impact

• Article: Metastatic cells can escape the proapoptotic effects of TNF-α through increased autocrine IL-6/STAT3 signaling.

  Shun Li, Ni Wang, Pnina Brodt
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  ABSTRACT: The liver is a common site for cancer metastases in which the entrance of tumor cells has been shown to trigger a rapid inflammatory response. In considering how an inflammatory response may affect metastatic colonization in this setting, we hypothesized that tumor cells may acquire resistance to the proapoptotic and tumoricidal effects of TNF-α, a cytokine that is elevated in a proinflammatory tissue microenvironment. In this study, we investigated molecular mechanisms by which such resistance may emerge using tumor cells in which the overexpression of the type I insulin-like growth factor receptor (IGF-IR) enhanced the inflammatory and metastatic capacities of poorly metastatic cells in the liver. Mechanistic investigations in vitro revealed that IGF-IR overexpression increased cell survival in the presence of high levels of TNF-α, in a manner associated with increased autocrine production of interleukin-6 (IL)-6. In turn, tumor cell-derived IL-6 induced gp130 and IL-6R-dependent activation of STAT3, leading to reduced caspase-3 activation and apoptosis. We found that IL-6 production and cell death resistance were dose dependent with increasing TNF-α levels. In addition, RNA interference-mediated knockdown of either IL-6 or gp130 that established a blockade to autocrine STAT3 induction was sufficient to abolish the prosurvival effect of TNF-α and to inhibit liver metastasis. Taken together, our findings define an IGF-IR-mediated mechanism of cancer cell survival that is critical for metastatic colonization of the liver.
  Cancer Research 12/2011; 72(4):865-75. · 7.86 Impact Factor
• Chapter: The Role of the IGF Axis in Human Malignancy: Evidence from Epidemiological Studies and Tissue Analysis

  Julia V. Burnier, Shun Li, Pnina Brodt
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  ABSTRACT: Clinical and experimental evidence obtained over the last three decades has collectively identified the insulin-like growth factor (IGF) axis as a major player in human cancer progression. This has led to a concerted effort to target the IGF axis, particularly the IGF-I receptor, for cancer therapy and has already resulted in the development of several inhibitors including insulin-like growth factor-I receptor (IGF-IR) antibodies and specific kinase inhibitors that have advanced into the clinic, with promising results. Detailed reviews on the role of the IGF-IR in malignancy based on animal studies and clinical evidence and on current therapeutic strategies for targeting the IGF axis are provided by other chapters in this collection. In this chapter, we review the epidemiological studies that have contributed to the identification of circulating IGF levels as a potential cancer risk factor and discuss possible reasons for, and the implications of, the disparity in the results obtained in different clinical studies. In addition, recent evidence, based on gene and protein arrays, that identifies IGF axis proteins as potential molecular regulators of tumor invasion is also reviewed highlighting the potential functional relevance of circulating and tumor-derived IGFs to cancer progression and metastasis.
  08/2011: pages 213-242;
• Chapter: Role of the IGF-Axis in Liver Metastasis: Experimental and Clinical Evidence

  Shun Li, Shoshana Yakar, Pnina Brodt
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  ABSTRACT: The insulin-like growth factors (IGF)-I and -II and their receptor IGF-IR play a major role during embryogenesis, development and pre-pubertal growth and in the maintenance of tissue homeostasis. A large and compelling body of evidence that accumulated over the past 2 decades has implicated this axis in tumorigenesis and the progression of malignant diseases. Here we summarize the evidence, based on experimental and clinical data that collectively identify the IGF-I receptor/ligand system as an important mediator of tumor metastasis in general, and liver metastasis in particular. We show that the IGF axis can be involved in each of the critical steps of the metastatic process by regulating cell-cell connectivity, tumor cell migration and invasion, angiogenesis and lymphangiogenesis and tumor cell survival and growth in distant sites, particularly the liver. We summarize clinical data based on genomic/proteomic analyses of clinical specimens that identify the IGF axis proteins as potential tumor biomarkers and indicators of advanced disease and review the pharmacological strategies that have been developed to target the IGF axis for anti-cancer therapy and their translational status. Taken together, the data provide a compelling rationale for the use of IGF – targeting strategies as a single modality or in combination with other drugs for prevention and treatment of metastatic disease. KeywordsMetastasis-Liver-IGF-Therapy
  12/2010: pages 233-271;
• Article: The IGF-I receptor can alter the matrix metalloproteinase repertoire of tumor cells through transcriptional regulation of PKC-{alpha}.

  Shun Li, Donglei Zhang, Long Yang, Julia V Burnier, Ni Wang, Rongtuan Lin, Eunice R Lee, Robert I Glazer, Pnina Brodt
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  ABSTRACT: The IGF-I receptor (IGF-IR) was identified as a tumor progression factor, but its role in invasion and metastasis has been the subject of some controversy. Previously we reported that in murine lung carcinoma M-27 cells, overexpression of IGF-IR increased the synthesis and activation of matrix metalloproteinase (MMP)-2 via Akt/phosphatidylinositol 3-kinase signaling. In contrast, we show here that in these and other cells, IGF-IR overexpression reduced the constitutive and phorbol 12-myristate 13-acetate (PMA)-inducible expression of three protein kinase C (PKC)-regulated metalloproteinases, MMP-3, MMP-9, and MMP-13, in cultured cells as well as in vivo in sc tumors. To elucidate the underlying mechanism, we analyzed the effect of IGF-IR on PKC expression and activity using wild-type and IGF-IR-overexpressing (M-27(IGFIR)) tumor cells. Our results show that overexpression and activation of IGF-IR reduced PKC-alpha expression, PKC activity, and downstream ERK1/2 signaling, and these effects were reversed in cells expressing kinase (Y(1131,1135,1136)F) or C-terminal (Y(1250/51)F) domain mutants of IGF-IR. This reduction was due to transcriptional down-regulation of PKC-alpha as evidenced by reduced PKC-alpha mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and a blockade of PKC-alpha promoter activation as revealed by a reporter gene assay. Finally, reconstitution of PKC-alpha levels could restore MMP-9 expression levels in these cells. Collectively, these results show that IGF-IR can inhibit PKC-alpha gene transcription and thereby block the synthesis of PMA-regulated MMPs, suggesting that within the same cells, IGF-IR can act as both a positive and negative regulator of MMP expression and function.
  Molecular Endocrinology 10/2009; 23(12):2013-25. · 4.54 Impact Factor