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Yin, Jinlong,Oh, Young Taek,Kim, Jeong-Yub,Kim, Sung Soo,Choi, Eunji,Kim, Tae Hoon,Hong, Jun Hee,Chang, Nakho,Cho, Hee Jin,Sa, Jason K.,Kim, Jeong Cheol,Kwon, Hyung Joon,Park, Saewhan,Lin, Weiwei,Naka American Association for Cancer Research 2017 Cancer research Vol.77 No.18
<P>Inhibition of a cellular enzyme that blocks the conversion from nonmesenchymal to mesenchymal forms of glioblastoma may prevent recurrence and resistance to radiation therapy, the latter of which continues to pose a major clinical challenge.</P><P>Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage–inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. <I>Cancer Res; 77(18); 4973–84. ©2017 AACR</I>.</P>
Yin, Jinlong,Park, Gunwoo,Kim, Tae Hoon,Hong, Jun Hee,Kim, Youn-Jae,Jin, Xiong,Kang, Sangjo,Jung, Ji-Eun,Kim, Jeong-Yub,Yun, Hyeongsun,Lee, Jeong Eun,Kim, Minkyung,Chung, Junho,Kim, Hyunggee,Nakano, I Public Library of Science 2015 PLoS biology Vol.13 No.5
<▼1><P>Epidermal growth factor receptor variant III (EGFRvIII) has been associated with glioma stemness, but the direct molecular mechanism linking the two is largely unknown. Here, we show that EGFRvIII induces the expression and secretion of pigment epithelium-derived factor (PEDF) via activation of signal transducer and activator of transcription 3 (STAT3), thereby promoting self-renewal and tumor progression of glioma stem cells (GSCs). Mechanistically, PEDF sustained GSC self-renewal by Notch1 cleavage, and the generated intracellular domain of Notch1 (NICD) induced the expression of Sox2 through interaction with its promoter region. Furthermore, a subpopulation with high levels of PEDF was capable of infiltration along corpus callosum. Inhibition of PEDF diminished GSC self-renewal and increased survival of orthotopic tumor-bearing mice. Together, these data indicate the novel role of PEDF as a key regulator of GSC and suggest clinical implications.</P></▼1><▼2><P>A permanently activated mutant form of the epidermal growth factor receptor found in glioblastoma promotes self-renewal and tumor progression by inducing autocrine signalling via pigment epithelium-derived factor (PEDF).</P></▼2><▼3><P><B>Author Summary</B></P><P>Malignant gliomas are among the most lethal types of cancer, due in part to the stem-cell-like characteristics and invasive properties of the brain tumor cells. However, little is known about the underlying molecular mechanisms that govern such processes. Here, we identify pigment epithelium-derived factor (PEDF) as a critical factor controlling stemness and tumor progression in glioma stem cells. We found that PEDF is secreted from glioblastoma expressing EGFRvIII, a frequently occurring mutation in primary glioblastoma that yields a permanently activated epidermal growth factor receptor. We delineate an EGFRvIII-STAT3-PEDF signaling axis as a signature profile of highly malignant gliomas, which promotes self-renewal of glioma stem cells. Our results demonstrate a previously unprecedented function of PEDF and implicate potential therapeutic approaches against malignant gliomas.</P></▼3>
Yin, Jinlong,Jung, Ji-Eun,Choi, Sun Il,Kim, Sung Soo,Oh, Young Taek,Kim, Tae-Hoon,Choi, Eunji,Lee, Sun Joo,Kim, Hana,Kim, Eun Ok,Lee, Yu Sun,Chang, Hee Jin,Park, Joo Yong,Kim, Yeejeong,Yun, Tak,Heo, K Elsevier 2018 Cancer letters Vol.414 No.-
<P><B>Abstract</B></P> <P>Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7-phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p-Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth <I>in vivo</I>. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC.</P> <P><B>Highlights</B></P> <P> <UL> <LI> BMP7-p-Smad1/5/8 signaling contributes to cetuximab resistance in OSCC. </LI> <LI> DMHI, a BMP signaling inhibitor, reduced cetuximab-resistant OSCC tumor growth. </LI> <LI> Combined treatment of DMH1 and cetuximab significantly reduced relapsed tumor growth <I>in vivo.</I> </LI> <LI> p-Smad1/5/8 overexpression in OSCC patients was associated with poor disease free survival. </LI> </UL> </P>
DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis
Yin, Jinlong,Park, Gunwoo,Lee, Jeong Eun,Choi, Eun Young,Park, Ju Young,Kim, Tae-Hoon,Park, Nayun,Jin, Xiong,Jung, Ji-Eun,Shin, Daye,Hong, Jun Hee,Kim, Hyunggee,Yoo, Heon,Lee, Seung-Hoon,Kim, Youn-Jae Oxford University Press 2015 Brain Vol.138 No.9
<P>Upregulation of microRNA-21 (miR-21) is strongly associated with glioma malignancy, but the regulatory mechanism that governs miR-21 biogenesis is unclear. Yin <I>et al.</I> demonstrate that the DEAD-box RNA helicase DDX23 promotes miR-21 biogenesis at the post-transcriptional level in glioma cells, and that DDX23 inhibition reduces glioma growth in mouse xenografts.</P><P> [Figure] </P><P>Upregulation of microRNA-21 (miR-21) is known to be strongly associated with the proliferation, invasion, and radio-resistance of glioma cells. However, the regulatory mechanism that governs the biogenesis of miR-21 in glioma is still unclear. Here, we demonstrate that the DEAD-box RNA helicase, DDX23, promotes miR-21 biogenesis at the post-transcriptional level. The expression of DDX23 was enhanced in glioma tissues compared to normal brain, and expression level of DDX23 was highly associated with poor survival of glioma patients. Specific knockdown of DDX23 expression suppressed glioma cell proliferation and invasion <I>in vitro</I> and <I>in vivo</I>, which is similar to the function of miR-21. We found that DDX23 increased the level of miR-21 by promoting primary-to-precursor processing of miR-21 through an interaction with the Drosha microprocessor. Mutagenesis experiments critically demonstrated that the helicase activity of DDX23 was essential for the processing (cropping) of miR-21, and we further found that ivermectin, a RNA helicase inhibitor, decreased miR-21 levels by potentially inhibiting DDX23 activity and blocked invasion and cell proliferation. Moreover, treatment of ivermectin decreased glioma growth in mouse xenografts. Taken together, these results suggest that DDX23 plays an essential role in glioma progression, and might thus be a potential novel target for the therapeutic treatment of glioma.</P>
Yue Yin,Xinyu Che,Zhenyu Li,Jinlong Li,Qinghua Han 한국강구조학회 2019 International Journal of Steel Structures Vol.19 No.6
Two micromechanical fracture models, void growth model (VGM) and stress modifi ed critical strain (SMCS) model, were adopted to distinguish the failure mechanism of welded hollow spherical (WHS) joints under axial load based on FE analysis. Ductile fracture was successfully predicted for WHS joints under axial tension. The predicted fracture location is at the weld toe between WHS joints and circular hollow section members, which is consistent with corresponding test results. The predicted fracture load is lower than the peak load on the load–displacement curve, which indicates that the failure mechanism of WHS joints under axial tension is fracture due to inadequate strength and the fracture load should be taken as the ultimate load bearing capacity of the joints. A simplifi ed SMCS model was proposed and verifi ed for ductile fracture prediction of WHS joints under axial tension. Micromechanical fracture analysis was also conducted on WHS joints under axial compression. It was obtained by both VGM and SMCS model that no fracture would occur before the load reached its peak value, the reason of which was discussed by tracing the variation of the equivalent plastic stain and stress triaxiality at the potential location of fracture. Therefore, the failure mechanism of WHS joints under axial compression is losing stability with the depression of the sphere cap and the peak load on the load–displacement curve should be taken as the ultimate load bearing capacity of WHS joints.
Park, Hye-Kyung,Hong, Jun-Hee,Oh, Young Taek,Kim, Sung Soo,Yin, Jinlong,Lee, An-Jung,Chae, Young Chan,Kim, Jong Heon,Park, Sung-Hye,Park, Chul-Kee,Park, Myung-Jin,Park, Jong Bae,Kang, Byoung Heon American Association for Cancer Research 2019 Cancer Research Vol.79 No.7
<P>Discovery and functional analysis of a TRAP1-SIRT3 complex in glioma stem cells identify potential target proteins for glioblastoma treatment.</P><P><B></B></P><P>Glioblastoma (GBM) cancer stem cells (CSC) are primarily responsible for metastatic dissemination, resistance to therapy, and relapse of GBM, the most common and aggressive brain tumor. Development and maintenance of CSCs require orchestrated metabolic rewiring and metabolic adaptation to a changing microenvironment. Here, we show that cooperative interplay between the mitochondrial chaperone TRAP1 and the major mitochondria deacetylase sirtuin-3 (SIRT3) in glioma stem cells (GSC) increases mitochondrial respiratory capacity and reduces production of reactive oxygen species. This metabolic regulation endowed GSCs with metabolic plasticity, facilitated adaptation to stress (particularly reduced nutrient supply), and maintained “stemness.” Inactivation of TRAP1 or SIRT3 compromised their interdependent regulatory mechanisms, leading to metabolic alterations, loss of stemness, and suppression of tumor formation by GSC <I>in vivo</I>. Thus, targeting the metabolic mechanisms regulating interplay between TRAP1 and SIRT3 may provide a novel therapeutic option for intractable patients with GBM.</P><P><B>Significance:</B></P><P>Discovery and functional analysis of a TRAP1–SIRT3 complex in glioma stem cells identify potential target proteins for glioblastoma treatment.</P>
Zhengyi Wu*,Liang Sun*,Ke Ning,Zhendong Chen,Zhipeng Wu,Hanqing Yang,Jinlong Yan*,Xiangbao Yin* 대한외과학회 2023 Annals of Surgical Treatment and Research(ASRT) Vol.105 No.6
Purpose: This study was performed to analyze the rule of confluence of the caudate lobe bile duct (CLD) into the left hepatic duct (LHD) and to discuss the protective strategy during left hemihepatectomy. Methods: MRI of 400 patients and T-tube angiography images of 100 patients were collected, and the imaging rules of the confluence of the CLD into the LHD were summarized. The clinical data of 33 patients who underwent left hemihepatectomy using the protective strategy were analyzed. Results: MRI and T-tube angiography images showed that the length from the confluence point of the CLD into the LHD to the confluence of the left and right hepatic ducts was 1.19 ± 0.40 cm and 1.26 ± 0.39 cm, respectively. The average angle between the longitudinal axis of the 2 bile ducts was 68.27° ± 22.59° and 66.58 ± 22.88°, respectively. Coronal and cross-sectional images showed that inflow from the foot side to the cranial side was noted in 79.8% and 82.0% of patients, respectively, and inflow from the dorsal to the ventral side was observed in 84.5% and 88.0%, respectively. Based on these imaging rules, the safe transection length and plane were summarized, and the CLD was effectively protected in 33 cases of left hemihepatectomy. Conclusion: In left hemihepatectomy, the LHD should be transected at least 1.5 cm away from the confluence of the left and right hepatic ducts, and the plane of transection should be oblique to the dorsal side at an angle of 45° with the LHD, these parameters represent an effective strategy to protect the CLD.