Objectives: The purpose of this study was to investigate bone morphogenetic protein (BMP)-2 expression following implantation of a statin and recombinant human BMP-2 (rhBMP-2), and to compare the bone regeneration capability of these substances in the rabbit nasal bone using immunohistological methods. Study design:Twelve adult male Japanese white rabbits (n = 12, age: 12-16 weeks, weight: 2.5-3.0 kg) were divided into three experimental groups and one control group.A total of 48 bone defects, four per rabbit, were created in the nasal bone while preserving the nasal membrane. In the experimental groups, one group was implanted with 10 mg statin dissolved in 0.2 ml water with an atelocollagen sponge (ACS), the second group was implanted with 5 μg rhBMP-2 with an ACS, and in the third group only the ACS was implanted. No material was implanted in the control group.Animals were killed at 1-, 2-, and 4-weeks postoperatively. The parts that had been operated on were removed and prepared for histological assessment. The expression of BMP-2 was evaluated using immunohistochemistry, and double-immunostaining for BMP-2 and Ki67 was observed by fluorescent microscopy.2

SUMMARY: Metallothionein (MT) is a ubiquitous protein with a low molecular weight of 6-7 kDa weight and it was first identified in the kidney cortex of equines as a cadmium (Cd)-binding protein responsible for the natural accumulation of Cd in the tissue. The mammalian MT contains 61 to 68 amino acid residues, in which 18 to 23 cysteine residues are present. The expression of MT starts by binding of metal transcription factor-1 (MTF-1) to the regulative region of MT gene called metal responsive elements (MREs). The induction of MT through the MREs region can be initiated by several metal ions such as zinc (Zn), copper (Cu) and Cd. However, Zn is the only heavy metal which can reversibly and directly activate the DNA-binding activity of MTF-1. In mammals four types of MT are expressed and they are termed metallothionein-1 (MT1), metallothionein-2 (MT2), metallothionein-3 (MT3), and metallothionein-4 (MT4). MT1 and MT2 are expressed in almost all tissues while MT3 and MT4 are tissue-specific. MT is a key compound involved in the intracellular handling of a variety of essential and nonessential post-transitional metal ions. In order to the heavy metal binding ability of MT, it is suggested to play roles both in the intracellular fixation of essential trace elements Zn and Cu, in controlling the concentrations, and in neutralizing the harmful influences of exposure to toxic elements.

It has been established that COX-2 and downstream signaling by prostaglandin E 2 (PGE 2 ) play a key role in tumorigenesis through generation of inflammatory microenvironment. Tolllike receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) also regulates inflammatory responses in tumors. However, the relationship between these distinct pathways in tumorigenesis is not yet fully understood. We herein investigated the role of MyD88 in gastric tumorigenesis using Gan mice, which develop inflammation-associated gastric tumors due to the simultaneous activation of the COX-2/PGE 2 pathway and Wnt signaling. Notably, the disruption of Myd88 in Gan mice resulted in the significant suppression of gastric tumorigenesis with the inhibition of inflammatory responses, even though COX-2/PGE 2 pathway is constitutively activated. Moreover, Myd88 disruption in bone marrow-derived cells (BMDCs) in Gan mice also suppressed inflammation and tumorigenesis, indicating that MyD88 signaling in BMDCs regulates the inflammatory microenvironment. We also found that expression of Tlr2 and its coreceptor Cd14 was induced in tumor epithelial cells in Gan mice, which was suppressed by the disruption of Myd88. It has already been shown that TLR2/CD14 signaling is important for stemness of intestinal epithelial cells. These results indicate that MyD88 in BMDCs, together with COX-2/PGE 2 pathway, plays an essential role in the generation of the inflammatory microenvironment, which may promote tumorigenesis through induction of TLR2/CD14 pathway in tumor epithelial cells. These results suggest that inhibition of TLR/MyD88 signaling together with COX-2/PGE 2 pathway will be an effective preventive strategy for gastric cancer.Cancer Prev Res; 9(3); 253-63. Ó2016 AACR.

Down‐regulation/mutation of AT‐rich interactive domain 1A (ARID1A), a novel tumor suppressor gene, has been reported in various cancers. Nevertheless, its role in renal cell carcinoma (RCC) remained unclear and underinvestigated. We thus evaluated carcinogenesis effects of ARID1A knockdown in nonmalignant Madin‐Darby canine kidney (MDCK) renal cells using small interfering RNA (siRNA) against ARID1A (siARID1A). The siARID1A‐transfected cells had decreased cell death, increased cell proliferation, and cell cycle shift (from G0/G1 to G2/M) compared with those transfected with controlled siRNA (siControl). Additionally, the siARID1A‐transfected cells exhibited epithelial‐mesenchymal transition (EMT) shown by greater spindle index, increased mesenchymal markers (fibronectin/vimentin), and decreased epithelial markers (E‐cadherin/zonula occludens‐1). Moreover, the siARID1A‐transfected cells had increases in migratory activity, nuclear size, self‐aggregated multicellular spheroid size, invasion capability, chemoresistance (to docetaxel), Snail family transcriptional repressor 1 expression, and TGF‐β1 secretion. All of these siARID1A‐knockdown effects on the carcinogenic features were reproducible in malignant RCC (786‐O) cells, which exhibited a higher degree of carcinogenic phenotypes compared with the nonmalignant MDCK cells. Finally, immunohistochemistry showed obvious decrease in ARID1A protein expression in human RCC tissues (n = 23) compared with adjacent normal renal tissues (n = 23). These data indicate that ARID1A down‐regulation triggers EMT and carcinogenesis features of renal cells in vitro, and its role in RCC could be proven in human tissues.—Somsuan, K., Peerapen, P., Boonmark, W., Plumworasawat, S., Samol, R., Sakulsak, N., Thongboonkerd, V. ARID1A knockdown triggers epithelial‐mesenchymal transition and carcinogenesis features of renal cells: role in renal cell carcinoma. FASEB J. 33, 12226‐12239 (2019). http://www.fasebj.org

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