Quantitative phosphoproteomic analysis identifies the potential therapeutic target EphA2 for overcoming sorafenib resistance in hepatocellular carcinoma cells

Chih-Ta Chen,Li-Zhu Liao,Ching-Hui Lu,Yung-Hsuan Huang,Yu-Kie Lin,Jung-Hsin Lin,Lu-Ping Chow 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-

Limited therapeutic options are available for advanced-stage hepatocellular carcinoma owing to its poor diagnosis. Drug resistance to sorafenib, the only available targeted agent, is commonly reported. The comprehensive elucidation of the mechanisms underlying sorafenib resistance may thus aid in the development of more efficacious therapeutic agents. To clarify the signaling changes contributing to resistance, we applied quantitative phosphoproteomics to analyze the differential phosphorylation changes between parental and sorafenib-resistant HuH-7 cells. Consequently, an average of ~1500 differential phosphoproteins were identified and quantified, among which 533 were significantly upregulated in resistant cells. Further bioinformatic integration via functional categorization annotation, pathway enrichment and interaction linkage analysis led to the discovery of alterations in pathways associated with cell adhesion and motility, cell survival and cell growth and the identification of a novel target, EphA2, in resistant HuH-7R cells. In vitro functional analysis indicated that the suppression of EphA2 function impairs cell proliferation and motility and, most importantly, overcomes sorafenib resistance. The attenuation of sorafenib resistance may be achieved prior to its development through the modulation of EphA2 and the subsequent inhibition of Akt activity. Binding analyses and in silico modeling revealed a ligand mimic lead compound, prazosin, that could abate the ligand-independent oncogenic activity of EphA2. Finally, data obtained from in vivo animal models verified that the simultaneous inhibition of EphA2 with sorafenib treatment can effectively overcome sorafenib resistance and extend the projected survival of resistant tumor-bearing mice. Thus our findings regarding the targeting of EphA2 may provide an effective approach for overcoming sorafenib resistance and may contribute to the management of advanced hepatocellular carcinoma.

Taiwanese Female Vegetarians Have Lower Lipoprotein-Associated Phospholipase A2 Compared with Omnivores

Chih-Wei Chen,Chin-Lon Lin,Chih-Ta Lin,Ying-Lung Lin,Tin-Kwang Lin 연세대학교의과대학 2011 Yonsei medical journal Vol.52 No.1

Purpose: Many studies supported that vegetarians have a lower risk of cardiac diseases and mortality, partly due to better blood pressure and serum cholesterol profiles. However, the inflammatory markers, especially lipoprotein-associated phospholipase A2 (Lp-PLA2), have not been well-studied. This study aimed to compare inflammatory markers and conventional risk factors between vegetarians and omnivores. Materials and Methods: One hundred and seventy-three vegetarians and 190 omnivores were studied. Fasting blood samples were obtained to compare levels of glucose, total cholesterol, triacylglycerol, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, homocysteine, Lp-PLA2 activity, and high-sensitivity C-reactive protein (hs-CRP). Results: Vegetarians had higher serum levels of the following markers: hs-CRP (1.8 ± 3.4 vs. 1.2 1.8 mg/L, respectively; p = 0.05), homocysteine (9.39 ± 3.22 vs. 7.62 ± 2.41 μmol/L, respectively; p < 0.01), and triacylglycerol (96.91 ± 59.56 vs. 84.66 ± 43.24 mg/dL, respectively; p < 0.05). Vegetarians also had lower levels of Lp-PLA2 (18.32 ± 7.19 10-3 μmol/min/mL vs. 20.22 8.13 10-3 μmol/min/mL; p < 0.05), total cholesterol (180.62 ± 36.55 mg/dL vs. 192.73 ± 36.57 mg/dL; p < 0.01), LDL cholesterol (118.15 ± 32.8 vs. 126.41 ± 34.28 mg/dL; p < 0.05), and HDL cholesterol (55.59 ± 13.30 vs. 62.09 ± 14.52 mg/dL, p < 0.01). Multivariate analyses demonstrated that a vegetarian diet increases the chances for high serum hs-CRP and low Lp-PLA2 activity. Conclusion: In addition to lower total cholesterol,LDL-cholesterol, and HDL-cholesterol, Taiwanese female vegetarians have lower serum Lp-PLA2 activity but higher levels of hs-CRP, homocysteine, and triacylglyerol. It might be due to geographic differences of vegetarian diets, and further studies are needed.

The economic burden of hip fractures in Asia

Ta-Wei Tai,Yu-Hsuan Lin,Chao-Jui Chang,Chih-Hsing Wu 대한골다공증학회 2021 Osteoporosis and Sarcopenia Vol.7 No.2

Significant down-regulation of growth hormone receptor expression revealed as a new unfavorable prognostic factor in hepatitis C virus-related hepatocellular carcinoma

( Ching-chih Lin ),( Ta-wei Liu ),( Ming-lun Yeh ),( Yi-shan Tsai ),( Pei-chien Tsai ),( Chung-feng Huang ),( Jee-fu Huang ),( Wan-long Chuang ),( Chia-yen Dai ),( Ming-lung Yu ) 대한간학회 2021 Clinical and Molecular Hepatology(대한간학회지) Vol.27 No.2

Background/Aims: Growth hormone (GH) is the main regulator of somatic growth, metabolism, and gender dimorphism in the liver. GH receptor (GHR) signaling in cancer is derived from a large body of evidence, although the GHR signaling pathway involved in the prognosis of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC, remains unclear. We aimed to explore the expression of GHR and analyze its association with clinicopathologic features and prognosis of patients with chronic hepatitis C and HCC. Methods: The expression of GHR mRNA was investigated by quantitative real-time polymerase chain reaction in paired tumors and adjacent non-tumorous (ANT) liver tissues of 200 patients with chronic hepatitis C and HCC. Western blotting and immunofluorescence assays using the HCV-infected Huh7.5.1 cell model was performed. Results: GHR mRNA was significantly lower in HCV-HCC tissues than in corresponding ANT liver tissues. GHR mRNA and protein levels also decreased in the HCV-infected Huh7.5.1 cell model. Notably, lower GHR expression was associated with age of >60 years (P=0.0111) and worse clinicopathologic characteristics, including alpha-fetoprotein >100 ng/mL (P=0.0403), cirrhosis (P=0.0075), vascular invasion (P=0.0052), pathological stage II-IV (P=0.0002), and albumin ≤4.0 g/dL (P=0.0055), which were linked with poor prognosis of HCC. Most importantly, the high incidence of recurrence and poor survival rates in patients with a low ratio of tumor/ANT GHR (≤0.1) were observed, indicating that low expression levels of GHR had great risk for development of HCC in patients with chronic hepatitis C. Conclusions: Our study demonstrates a significant down-regulation of GHR expression as a new unfavorable independent prognostic factor in patients with chronic hepatitis C and HCC. (Clin Mol Hepatol 2021;27:313-328)

The in vivo photothermal treatment of gold nanorod in the mouse ear model

Liu, Bruce Yao Wen,Chen, Cheng-Lung,Lee, Shin-Yu,Chang, Fu-Hsiung,Lin, Win-Li,Chia, Chih-Ta,Chen, Yang-Yuan Techno-Press 2014 Biomaterials and biomedical engineering Vol.1 No.1

Gold nanorod's exceptional light to heat transduction is a robust phonomenon that has been extensively verified. The phenomenon is a trait from which many novel applications across disciplines have been proposed. In this investigation, the feasibility of utilizing heat harvested from such photothermal method to combat cancer is presented. Using non-invasive laser methods, an in vivo study is conducted on mouse ear tumors administered with gold nanorods (Au NRs). An emphasis is placed on monitoring the tumor developments after photothermal treatments, over time. The findings reveal significant tumor growth surpression at a threshold laser power of $0.6W/cm^2$ lasting 2 minutes; this energy also brought about dramatic size reduction in treated tumors. Furthermore, the apparent formation of an eschar over the laser treated region indicates extensive hemorrhagic necrosis of the tumor tissue; a phenomenon implicative to the inhibition of angiogenesis.

The in vivo photothermal treatment of gold nanorod in the mouse ear model

Liu, Bruce Yao Wen,Chen, Cheng-Lung,Lee, Shin-Yu,Chang, Fu-Hsiung,Lin, Win-Li,Chia, Chih-Ta,Chen, Yang-Yuan Techno-Press 2014 Biomaterials and Biomechanics in Bioengineering Vol.1 No.1

Gold nanorod's exceptional light to heat transduction is a robust phonomenon that has been extensively verified. The phenomenon is a trait from which many novel applications across disciplines have been proposed. In this investigation, the feasibility of utilizing heat harvested from such photothermal method to combat cancer is presented. Using non-invasive laser methods, an in vivo study is conducted on mouse ear tumors administered with gold nanorods (Au NRs). An emphasis is placed on monitoring the tumor developments after photothermal treatments, over time. The findings reveal significant tumor growth surpression at a threshold laser power of $0.6W/cm^2$ lasting 2 minutes; this energy also brought about dramatic size reduction in treated tumors. Furthermore, the apparent formation of an eschar over the laser treated region indicates extensive hemorrhagic necrosis of the tumor tissue; a phenomenon implicative to the inhibition of angiogenesis.