Jou-Ho Shih

All Publications

• Early prediction of 1-year tumor response of hepatocellular carcinoma with lipiodol deposition pattern through post-embolization cone-beam computed tomography during conventional transarterial chemoembolization. European radiology Tsai, Y., Shih, J., Hwang, H., Chiu, N., Lee, R., Tseng, H., Liu, C. 2021

  Abstract

  OBJECTIVE: To evaluate whether parenchyma-to-lipiodol ratio (PLR) and lesion-to-lipiodol ratio (LLR) on C-arm cone-beam computed tomography (CBCT) can predict 1-year tumor response in patients with hepatocellular carcinoma (HCC) treated with conventional transcatheter arterial chemoembolization (cTACE).METHODS: This retrospective analysis included 221 HCC target lesions within up-to-seven criteria in 80 patients who underwent cTACE with arterial-phase CBCT and unenhanced CBCT after cTACE from 2015 to 2018. PLR and LLR of every tumor slice were obtained through mean density division of liver parenchyma and tumor enhancement with intratumoral lipiodol deposition. The cutoff values (COVs) of maximal PLR and LLR of every tumor were analyzed using Youden's index. The reliability of COV, correlations between the related parameters, and 1-year progression were assessed through interobserver agreement and multivariate analysis. COV validity was verified using the chi-square test and Cramer's V coefficient (V) in the validation cohort.RESULTS: Standard COVs of PLR and LLR were 0.149 and 1.4872, respectively. Interobserver agreement of COV for PLR and LLR was near perfect (kappa > 0.9). Multivariate analysis suggested that COV of PLR is an independent predictor (odds ratio = 1.23532*1014, p = 4.37*10-7). COV of PLR showed strong consistency, correlation with 1-year progression in prediction model (V = 0.829-0.776; p < 0.0001), and presented as an effective predictor in the validation cohort (V = 0.766; p < 0.0001).CONCLUSION: The COV of PLR (0.149) assessed through immediate post-embolization CBCT is an objective, effective, and approachable predictor of 1-year HCC progression after cTACE.KEY POINTS: The maximal PLR value indicates the least lipiodol-distributed region in an HCC tumor. The maximal LLR value indicates the least lipiodol-deposited region in the tumor due to incomplete lipiodol delivery. PLR and LLR are concepts like signal-to-noise ratio to characterize the lipiodol retention pattern objectively to predict 1-year tumor progression immediately without any quantification software for 3D image analysis immediately after cTACE treatment. COV of PLR can facilitate the early prediction of tumor progression/recurrence and indicate the section of embolized HCC, providing the operator's good targets for sequential cTACE or combined ablation. The validation cohort in our study verified standard COVs of PLR and LLR. The validation process was more convincing and delicate than that of previous retrospective studies.

  View details for DOI 10.1007/s00330-021-07843-8

  View details for PubMedID 33765160

• Usp11 controls cortical neurogenesis and neuronal migration through Sox11 stabilization. Science advances Chiang, S. Y., Wu, H. C., Lin, S. Y., Chen, H. Y., Wang, C. F., Yeh, N. H., Shih, J. H., Huang, Y. S., Kuo, H. C., Chou, S. J., Chen, R. H. 2021; 7 (7)

  Abstract

  The role of protein stabilization in cortical development remains poorly understood. A recessive mutation in the USP11 gene is found in a rare neurodevelopmental disorder with intellectual disability, but its pathogenicity and molecular mechanism are unknown. Here, we show that mouse Usp11 is expressed highly in embryonic cerebral cortex, and Usp11 deficiency impairs layer 6 neuron production, delays late-born neuronal migration, and disturbs cognition and anxiety behaviors. Mechanistically, these functions are mediated by a previously unidentified Usp11 substrate, Sox11. Usp11 ablation compromises Sox11 protein accumulation in the developing cortex, despite the induction of Sox11 mRNA. The disease-associated Usp11 mutant fails to stabilize Sox11 and is unable to support cortical neurogenesis and neuronal migration. Our findings define a critical function of Usp11 in cortical development and highlight the importance of orchestrating protein stabilization mechanisms into transcription regulatory programs for a robust induction of cell fate determinants during early brain development.

  View details for DOI 10.1126/sciadv.abc6093

  View details for PubMedID 33579706

  View details for PubMedCentralID PMC7880594

• Targeting protein tyrosine phosphatase PTP-PEST (PTPN12) for therapeutic intervention in acute myocardial infarction. Cardiovascular research Yang, C. F., Chen, Y. Y., Singh, J. P., Hsu, S. F., Liu, Y. W., Yang, C. Y., Chang, C. W., Chen, S. N., Shih, R. H., Hsu, S. D., Jou, Y. S., Cheng, C. F., Meng, T. C. 2020; 116 (5): 1032-1046

  Abstract

  The myocardial ischaemia/reperfusion (I/R) injury is almost inevitable since reperfusion is the only established treatment for acute myocardial infarction (AMI). To date there is no effective strategy available for reducing the I/R injury. Our aim was to elucidate the mechanisms underlying myocardial I/R injury and to develop a new strategy for attenuating the damage it causes.Using a mouse model established by ligation of left anterior descending artery, we found an increase in activity of protein tyrosine phosphatases (PTPs) in myocardium during I/R. Treating the I/R-mice with a pan-PTP inhibitor phenyl vinyl sulfone attenuated I/R damage, suggesting PTP activation to be harmful in I/R. Through analysing RNAseq data, we showed PTPs being abundantly expressed in mouse myocardium. By exposing primary cardiomyocytes ablated with specific endogenous PTPs by RNAi to hypoxia/reoxygenation (H/R), we found a role that PTP-PEST (PTPN12) plays to promote cell death under H/R stress. Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis, may target PTP-PEST thus suppressing its activity. We elucidated the molecular basis for Auranofin-induced inactivation of PTP-PEST by structural studies, and then examined its effect on myocardial I/R injury. In the mice receiving Auranofin before reperfusion, myocardial PTP activity was suppressed, leading to restored phosphorylation of PTP-PEST substrates, including ErbB-2 that maintains the survival signalling of the heart. In line with the inhibition of PTP-PEST activity, the Auranofin-treated I/R-mice had smaller infarct size and better cardiac function.PTP-PEST contributes to part of the damages resulting from myocardial I/R. The drug Auranofin, potentially acting through the PTP-PEST-ErbB-2 signalling axis, reduces myocardial I/R injury. Based on this finding, Auranofin could be used in the development of new treatments that manage I/R injury in patients with AMI.

  View details for DOI 10.1093/cvr/cvz165

  View details for PubMedID 31228185

• Integrative analyses of noncoding RNAs reveal the potential mechanisms augmenting tumor malignancy in lung adenocarcinoma. Nucleic acids research Shih, J. H., Chen, H. Y., Lin, S. C., Yeh, Y. C., Shen, R., Lang, Y. D., Wu, D. C., Chen, C. Y., Chen, R. H., Chou, T. Y., Jou, Y. S. 2020; 48 (3): 1175-1191

  Abstract

  Precise noncoding RNA (ncRNA)-based network prediction is necessary to reveal ncRNA functions and pathological mechanisms. Here, we established a systemic pipeline to identify prognostic ncRNAs, predict their functions and explore their pathological mechanisms in lung adenocarcinoma (LUAD). After in silico and experimental validation based on evaluations of prognostic value in multiple LUAD cohorts, we selected the PTTG3P pseudogene from among other prognostic ncRNAs (MIR497HG, HSP078, TBX5-AS1, LOC100506990 and C14orf64) for mechanistic studies. PTTG3P upregulation in LUAD cells shortens the metaphase to anaphase transition in mitosis, increases cell viability after cisplatin or paclitaxel treatment, facilitates tumor growth that leads to poor survival in orthotopic lung models, and is associated with a poor survival rate in LUAD patients in the TCGA cohort who received chemotherapy. Mechanistically, PTTG3P acts as an ncRNA that interacts with the transcription factor FOXM1 to regulate the transcriptional activation of the mitotic checkpoint kinase BUB1B, which augments tumor growth and chemoresistance and leads to poor outcomes for LUAD patients. Overall, we established a systematic strategy to uncover prognostic ncRNAs with functional prediction methods suitable for pan-cancer studies. Moreover, we revealed that PTTG3P, due to its upregulation of the PTTG3P/FOXM1/BUB1B axis, could be a therapeutic target for LUAD patients.

  View details for DOI 10.1093/nar/gkz1149

  View details for PubMedID 31853539

  View details for PubMedCentralID PMC7026595

• PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression. Nature communications Lang, Y. D., Chen, H. Y., Ho, C. M., Shih, J. H., Hsu, E. C., Shen, R., Lee, Y. C., Chen, J. W., Wu, C. Y., Yeh, H. W., Chen, R. H., Jou, Y. S. 2019; 10 (1): 5716

  Abstract

  Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/β-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/β-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy.

  View details for DOI 10.1038/s41467-019-13665-6

  View details for PubMedID 31844057

  View details for PubMedCentralID PMC6914800

• Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma. World journal of gastroenterology Gu, D. L., Chen, Y. H., Shih, J. H., Lin, C. H., Jou, Y. S., Chen, C. F. 2013; 19 (47): 8873-9

  Abstract

  High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma (HCC) cohorts confirmed previously identified frequently mutated somatic genes, such as TP53, CTNNB1 and AXIN1, and identified several novel genes with moderate mutation frequencies, including ARID1A, ARID2, MLL, MLL2, MLL3, MLL4, IRF2, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3, JAK1, KEAP1, NFE2L2, C16orf62, LEPR, RAC2, and IL6ST. Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling, Wnt/β-catenin signaling, JAK/STAT signaling, and oxidative stress play critical roles in HCC tumorigenesis. Nevertheless, because there are few druggable genes used in HCC therapy, the identification of new therapeutic targets through integrated genomic approaches remains an important task. Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain, copy number alteration (CNA) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons, homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression. Moreover, integration of CNAs with other high-throughput genomic data, such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models, provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.

  View details for DOI 10.3748/wjg.v19.i47.8873

  View details for PubMedID 24379610

  View details for PubMedCentralID PMC3870538