Proteomic Characterization of the World Trade Center dust-activated mdig and c-myc signaling circuit linked to multiple myeloma

Abstract

Several epidemiological studies suggested an increased incidence rate of multiple myeloma (MM) among first responders and other individuals who exposed to World Trade Center (WTC) dust. In this report, we provided evidence showing that WTC dust is potent in inducing mdig protein and/or mRNA in bronchial epithelial cells, B cells and MM cell lines. An increased mdig expression in MM bone marrow was observed, which is associated with the disease progression and prognosis of the MM patients. Through integrative genomics and proteomics approaches, we further demonstrated that mdig directly interacts with c-myc and JAK1 in MM cell lines, which contributes to hyperactivation of the IL-6-JAK-STAT3 signaling important for the pathogenesis of MM. Genetic silencing of mdig reduced activity of the major downstream effectors in the IL-6-JAK-STAT3 pathway. Taken together, these data suggest that WTC dust may be one of the key etiological factors for those who had been exposed for the development of MM by activating mdig and c-myc signaling circuit linked to the IL-6-JAK-STAT3 pathway essential for the tumorigenesis of the malignant plasma cells.

The emerging roles of ribosomal histidyl hydroxylases in cell biology, physiology and disease

“…There are now several reports describing MINA overexpression in multiple cancer types including colorectal [ 54 ], lung [ 30 , 55 ], esophageal [ 56 ], lymphoma [ 57 ], cholangiocarcinoma [ 58 ], gingival squamous cell carcinoma [ 59 ], neuroblastoma [ 60 ], liver [ 61 , 62 ], gastric [ 63 ], pancreatic [ 64 ], multiple myeloma [ 65 ], and breast cancers [ 66 ]. Importantly, MINA expression was associated with poor prognosis in some, but not all, of these studies [ 56 , 60 , 63 , 65 – 67 ]. Interestingly, MINA overexpression positively correlated with immunohistochemical markers of proliferation in several studies [ 58 – 60 , 62 , 67 ].…”

World Trade Center Health Program: First Decade of Research

“…Consequentially, cancer research accounts for a large portion (21%) of the funds awarded. There are descriptive and analytic studies examining cancer mortality and incidence, with a few studies examining mechanisms or treatment [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. There are also notable reviews [ 77 , 78 ].…”

“…Another study indicated WTC-dusts are highly capable of inducing mdig (mineral dust-induced gene, also known as mina53, MINA, or NO52) in normal B cells and malignant myeloma cell lines. The levels of mdig mRNA and protein are associated with multiple myeloma progression and prognosis [ 74 ]. Still, the current evidence of increased multiple myeloma in WTC populations is inconsistent.…”

“…Additional molecular studies focusing on mechanisms may inform etiology, pathophysiology, and ultimately aid clinical management. For example, further exploration of mdig expression may result in its use as a prognostic marker to guide multiple myeloma treatments [ 74 ].…”

Molecular Signatures of JMJD10/MINA53 in Gastric Cancer

“…Increasing evidence also suggests that JMJD10 has lysine-(K) demethylase (KDM) activity in various experimental conditions. In particular, studies have reported the involvement of JMJD10/MINA53 in histone methylation by antagonizing trimethyl lysine 9 on histone H3 (H3K9me3) [7][8][9][10][11][12][13][14][15]. Later studies indicated that JMJD10/MINA53 was also involved in the repression of H3K36me3 [16], H3K27me3, and H4K20me3 [17].…”