β2-Microglobulin Is a Signaling and Growth-Promoting Factor for Human Prostate Cancer Bone Metastasis

Huang, Wen-Chin; Wu, Daqing; Xie, Zhihui; Zhau, Haiyen E.; Nomura, Takeo; Zayzafoon, Majd; Pohl, Jan; Hsieh, Chia Ling; Weitzmann, M. Neale; Farach-Carson, Mary C.; Chung, Leland W.K.

doi:10.1158/0008-5472.can-06-1996

Cited by 104 publications

(121 citation statements)

References 43 publications

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“…Selective activation of CREB could promote local tumor growth and distant metastasis (Huang et al, 2006;Melnikova et al, 2006). Many modulators of CREB activity are abundant in bone tissues, such as stromal cell-derived factor-1, fibroblast growth factor, transformation growth factor (Johannessen et al, 2004) and b-2-microglobulin (Huang et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…In human prostate cancer (PCa), CREB may promote acquisition of neuroendocrine differentiation, associated with androgen-independent progression (Chen et al, 1999;Deeble et al, 2001). Previous studies from our laboratory and others indicated that CREB signaling regulated osteomimicry in PCa bone metastasis, conferring tumor survival and growth advantages in the bone microenvironment (Huang et al, 2006). Our results demonstrated that b-2 microglobulin activation of protein kinase A (PKA)-CREB signaling resulted in increased expression of osteocalcin and bone sialoprotein and conferred explosive PCa growth in bone.…”

Section: Introductionmentioning

confidence: 99%

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cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis

et al. 2007

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Aberrant expression of vascular endothelial growth factor (VEGF) is associated with human prostate cancer (PCa) metastasis and poor clinical outcome. We found that both phosphorylation of cyclic AMP-responsive element-binding protein (CREB) and VEGF levels were significantly elevated in patient bone metastatic PCa specimens. A PCa ARCaP progression model demonstrating epithelial-tomesenchymal transition exhibited increased CREB phosphorylation and VEGF expression as ARCaP cells became progressively more mesenchymal and bone-metastatic. Activation of CREB induced, whereas inhibition of CREB blocked, VEGF expression in ARCaP cells. CREB may regulate VEGF transcription via a hypoxia-inducible factor-dependent mechanism in normoxic conditions. Activation of CREB signaling is involved in the coordinated regulation of VEGF and may pre-dispose to PCa bone metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis

et al. 2007

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“…27 In brief, three groups of six mice each were inoculated subcutaneously with 5 Â 10 6 A549 cells in 200 ml of phosphate-buffered saline at a single dorsal site. After 2 weeks, the tumor-bearing mice were treated with an intratumoral injection every 2 days for 2 weeks as follows: the group 'control', 20 ml of sterilized 0.9% (w/v) NaCl solution for each mouse; group 'NC', 0.8 mg of nonspecific scramble siRNA mixed with 19.2 ml of Lipofectamine2000 for each mouse; and group 'si', 0.8 mg of PC4 specific siRNA mixed with 19.2 ml of Lipofectamine2000 for each mouse.…”

Section: Tumor Model In Nude Micementioning

confidence: 99%

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

et al. 2012

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Transcriptional positive coactivator 4 (PC4) is a multifunctional nuclear protein that has important roles in DNA transcription, replication, repair and heterochromatinization. However, the role of PC4 in cancer remains to be clarified. Several studies propose that PC4 may act as a putative tumor suppressor. Here, we demonstrate for the first time that PC4 may represent a potential therapeutic target in non-small cell lung cancer (NSCLC). PC4 protein expression is significantly upregulated in NSCLC carcinoma tissues compared with their adjacent noncancerous counterparts as shown by immunohistochemical staining and western blotting in 104 pairs of formalin-fixed human NSCLC specimens and 6 fresh NSCLC samples. Knockdown of PC4 expression by sequence-specific small interfering RNA (siRNA) in human NSCLC cells (A549, H460 and H358) significantly inhibits the growth of cancer cells by the induction of cell cycle arrest and the increase of cell apoptosis in vitro. Interrupting the PC4 signaling pathway by injection of the PC4 siRNA liposome complex produced an effective regression of pre-established A549 cell xenografts in mice through growth inhibition and increased apoptosis. These results indicated that PC4 could be an attractive new therapeutic target for the treatment of NSCLC.

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“…2-m has been reported by our laboratory and others to be a growth-stimulating factor and cell signaling molecule in several types of cancer cells [30][31][32][33]. We reported that 2-m played multiple roles in cancer development and mediates tumorigenesis, angiogenesis, and osteomimicry [30,31,34].…”

Section: Introductionmentioning

confidence: 69%

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2014

ScienceOpen Research

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2-microglobulin ( 2-m) has become the focus of intense scrutiny since the discovery of its undesirable roles promoting osteomimicry and cancer progression. 2-m is a well-known housekeeping protein that forms complexes with the heavy chain of major histocompatibility complex class I molecules, which are heterodimeric cell surface proteins that present antigenic peptides to cytotoxic T cells. On recognition of foreign peptide antigens on cell surfaces, T cells actively bind and lyse antigen-presenting cancer cells. In addition to its roles in tumor immunity, 2-m has two different functions in cancer cells, either tumor promoting or tumor suppressing, in cancer cell context-dependent manner. Our studies have demonstrated that 2-m is involved extensively in the functional regulation of growth, survival, apoptosis, and even metastasis of cancer cells. We found that 2-m is a soluble growth factor and a pleiotropic signaling molecule which interacts with its receptor, hemochromatosis protein, to modulate epithelial-to-mesenchymal transition (EMT) through iron-responsive pathways. Specific antibodies against 2-m have remarkable tumoricidal activity in cancer, through 2-m action on iron flux, alterations of intracellular reactive oxygen species, DNA damage and repair enzyme activities, -catenin activation and cadherin switching, and tumor responsiveness to hypoxia. These novel functions of 2-m and 2-m signaling may be common to several solid tumors including human lung, breast, renal, and prostate cancers. Our experimental results could lead to the development of a novel class of antibody-based pharmaceutical agents for cancer growth control. In this review, we briefly summarize the recent data regarding 2-m as a promising new cancer therapeutic target and discuss antagonizing this therapeutic target with antibody therapy for the treatment of localized and disseminated cancers.Keywords: Anti-2-m antibody, apoptosis, 2-microglobulin ( 2-m), osteomimicry. INTRODUCTION2-microglobulin ( 2-m), a well-known housekeeping gene, is a nonglycosylated protein with a low molecular weight of 12-kDa. This 99-amino acid residue protein is synthesized by all nucleated cells. It has been identified as a major structural component of amyloid fibrils deposited in dialysis-related amyloidosis, a common and serious complication in patients receiving hemodialysis for more than 10 years [1, 2]. 2-m forms a small invariable light chain subunit of the major histocompatibility complex (MHC) class I antigen, also known as human leukocyte antigen (HLA), on the cell surface of nucleated cells. 2-m is an important structural protein in the regulation of host immune recognition of self and non-self antigens by CD8 + T lymphocytes and for immunoglobulin transport and iron metabolism [3][4][5][6]. Some animal studies have reported that even when no MHC class I antigens could be detected on cells and the animals were grossly deficient in CD4 -CD8 + T cells, which normally mediate cytotoxic T cell function, the homozygotes appeared normal [7,8]....

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β2-Microglobulin Is a Signaling and Growth-Promoting Factor for Human Prostate Cancer Bone Metastasis

Cited by 104 publications

References 43 publications

cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis

cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

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