High Mobility Group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein which acts as a transcriptional regulating factor involved in gene transcription. In particular, overexpression of HMGA2 has been demonstrated to associate with neoplastic transformation and tumor progression in Colorectal Cancer (CRC). Thus, HMGA2 is a potential therapeutic target in cancer therapy. Heat Shock Protein 90 (Hsp90) is a chaperone protein required for the stability and function for a number of proteins that promote the growth, mobility, and survival of cancer cells. Moreover, it has shown strong positive connections were observed between Hsp90 inhibitors and CRC, which indicated their potential for use in CRC treatment by using combination of data mining and experimental designs. However, little is known about the effect of Hsp90 inhibition on HMGA2 protein expression in CRC. In this study, we tested the hypothesis that Hsp90 may regulate HMGA2 expression and investigated the relationship between Hsp90 and HMGA2 signaling. The use of the second-generation Hsp90 inhibitor, NVP-AUY922, considerably knocked down HMGA2 expression, and the effects of Hsp90 and HMGA2 knockdown were similar. In addition, Hsp90 knockdown abrogates colocalization of Hsp90 and HMGA2 in CRC cells. Moreover, the suppression of HMGA2 protein expression in response to NVP-AUY922 treatment resulted in ubiquitination and subsequent proteasome-dependant degradation of HMGA2. Furthermore, RNAi-mediated silencing of HMGA2 reduced the survival of CRC cells and increased the sensitivity of these cells to chemotherapy. Finally, we found that the NVP-AUY922-dependent mitigation of HMGA2 signaling occurred also through indirect reactivation of the tumor suppressor microRNA (miRNA), let-7a, or the inhibition of ERK-regulated HMGA2 involved in regulating the growth of CRC cells. Collectively, our studies identify the crucial role for the Hsp90-HMGA2 interaction in maintaining CRC cell survival and migration. These findings have significant implications for inhibition HMGA2-dependent tumorigenesis by clinically available Hsp90 inhibitors.
Hernia sac ligation was associated with higher postoperative pain, and did not show any benefit over sac nonligation regarding the incidence of recurrence and postoperative complications in patients undergoing open tension-free mesh repair or laparoscopic procedures.
In this paper, we first demonstrate the control of the film pore size using neutral hydrophilic 2-hydroxyethyl methacrylate (HEMA) content. To improve the mechanical properties of a polyampholyte (PA), both HEMA and the cross-linker N,N′methylenebisacrylamide (Bis-Am) were introduced into the PA chain. The predesigned copolymers showed great mechanical properties and optical behavior. The introduction of HEMA significantly increased the water content of the polymer, leading to the formation of porous structures in xerogels. The dynamic interaction between the positive and negative termini of the PA endowed the hydrogels with self-healing ability. The synthesized chemically cross-linked PA gels showed high stability in saline solution. The biocompatibility of the PA gels was confirmed using a cytotoxicity test of cells attached to the synthesized PA-X-2 and PA/HEMA-90/10-X-0.5. The results of this investigation indicate that the synthesized PA gels are applicable as a polymeric scaffold for cell culture.
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