β2-Microglobulin Induces Epithelial to Mesenchymal Transition and Confers Cancer Lethality and Bone Metastasis in Human Cancer Cells

Abstract

Bone metastasis is one of the predominant causes of cancer lethality. This study demonstrates for the first time how β2-microglobulin (β2-M) supports lethal metastasis in vivo in human prostate, breast, lung and renal cancer cells. β2-M mediates this process by activating epithelial to mesenchymal transition (EMT) to promote lethal bone and soft tissue metastases in host mice. β2-M interacts with its receptor, hemochromatosis (HFE) protein, to modulate iron responsive pathways in cancer cells. Inhibition of either β2-M or HFE results in reversion of EMT. These results demonstrate the role of β2-M in cancer metastasis and lethality. Thus, β2-M and its downstream signaling pathways are promising prognostic markers of cancer metastases and novel therapeutic targets for cancer therapy.

Epidermal Growth Factor Promotes Protein Degradation of Epithelial Protein Lost in Neoplasm (EPLIN), a Putative Metastasis Suppressor, during Epithelial-mesenchymal Transition

“…Upon exposure to certain soluble factors or host bone microenvironment, low-invasive and epithelial-like ARCaP E cells undergo EMT and acquire invasive properties (26,27). Western blot analysis showed that both EGFR and neu (HER2/ ErbB2) were highly expressed and phosphorylated in ARCaP E cells and their highly metastatic, mesenchymal-like counterparts ARCaP M cells (Fig.…”

Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors

“…Although it is generally accepted that the immune system plays a role in PCa, the exact mechanism by which the immune system is involved in PCa initiation, progression and treatment remains unclear. 41,44 Sipuleucel-T has been approved by the US FDA as a cellular immunotherapy that improves overall survival in asymptomatic or minimally symptomatic metastatic castrate-resistant PCa patients, and other immunotherapies such as ipilimumab are in advanced stages of clinical development. 45,46 However, some have doubted its efficacy.…”

Test Article

“…The 2-m/HFE complex protects against the influx and accumulation of intracellular iron and negatively regulates intracellular iron concentration in cancer cells, mediated by 2-m/HFE complex interaction with transferrin receptor (TFR) [38,39]. We also found that lower levels of intracellular iron concentration caused by the 2-m/HFE complex activate hypoxia inducible factor-1 (HIF-1 ) and induce overexpression of its downstream target genes in cancer cells, driving EMT and promoting cancer lethal bone and soft tissue metastases [34]. This cell signaling network is highly conserved in human prostate, kidney, lung, and breast cancer cells, with activation of 2-m/HFE complex resulting in the induction of EMT, the lethal progression of these cancers to host bone and soft tissues and ultimately the demise of the host.…”

“…We reported that 2-m played multiple roles in cancer development and mediates tumorigenesis, angiogenesis, and osteomimicry [30,31,34]. 2-m is also known to promote the growth and survival of stromal cells, such as mesenchymal stem cells (MSCs), osteoblasts, and osteoclasts supporting cancer bone metastasis [31,[35][36][37].…”

“…These distinctive roles may make the 2-m-mediated cell signaling network a highly desirable therapeutic target. To uncover the 2-m-meditated intracellular signaling network, we identified the hemochromatosis (HFE) protein as a 2-m receptor [34]. HFE is a non-classical MHC class I molecule that complexes with 2-m.…”