Shing Hooi - Profile on Academia.edu (original) (raw)

Papers by Shing Hooi

Experimental and Molecular Medicine, Nov 16, 2022

Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-... more Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.

On the interations of galanin within the hypothalamic-pituitary axis of the rat

The hypothalamus has been shown to be densely populated by galanin-containing neuron cell bodies.... more The hypothalamus has been shown to be densely populated by galanin-containing neuron cell bodies. The greatest concentration of cells reside in the arcuate nucleus. In addition, galanin immunopositive cells are present in the paraventricular (PVN), supraoptic (SON) and dorsomedial nuclei (Rokaeus et al., 1984; Ch’ng et al., 1985; Skofitsch et al., 1985; Melander et al., 1985, 1986; Palkovits et al., 1987). Galanin-containing nerve fibers are found throughout the hypothalamus but the median eminence (ME) contains the highest concentration of galanin in the brain (Skofitsch et al., 1986; Gabriel et al., 1988). Autoradiographic binding studies also demonstrated that galanin receptors are concentrated in the ME (Melander et al., 1986; Skofitsch et al., 1987). Much of the galanin in the ME originates in the arcuate nucleus (Gabriel et al., 1988) but the PVN and SON also contribute substantial amounts of galanin to the ME (Palkovits et al., 1987). Furthermore, Levin et al. (1987) and Holets et al. (1988) demonstrated that brainstem neurons containing galanin project to both the PVN and SON. These inputs probably relay hemodynamic information to these nuclei.

Acetyl-keto-β-boswellic acid down-regulates G1 phase cyclin/CDKs and inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells

Cancer Research, Apr 15, 2006

Data from FOXQ1 Regulates Epithelial-Mesenchymal Transition in Human Cancers

Epithelial-mesenchymal transition (EMT) in cancer cells plays a pivotal role in determining metas... more Epithelial-mesenchymal transition (EMT) in cancer cells plays a pivotal role in determining metastatic prowess, but knowledge of EMT regulation remains incomplete. In this study, we defined a critical functional role for the Forkhead transcription factor FOXQ1 in regulating EMT in breast cancer cells. FOXQ1 expression was correlated with high-grade basal-like breast cancers and was associated with poor clinical outcomes. RNAi-mediated suppression of FOXQ1 expression in highly invasive human breast cancer cells reversed EMT, reduced invasive ability, and alleviated other aggressive cancer phenotypes manifested in 3-dimensional Matrigel (BD Biosciences) culture. Conversely, enforced expression of FOXQ1 in differentiated human mammary epithelial cells (HMLER) or epithelial cancer cell lines provoked an epithelial to mesenchymal morphologic change, gain of stem cell–like properties, and acquisition of resistance to chemotherapy-induced apoptosis. Mechanistic investigations revealed that FOXQ1-induced EMT was associated with transcriptional inactivation of the epithelial regulator E-cadherin (CDH1). Our findings define a key role for FOXQ1 in regulating EMT and aggressiveness in human cancer. Cancer Res; 71(8); 3076–86. ©2011 AACR.

Supplementary Table 3 from FOXQ1 Regulates Epithelial-Mesenchymal Transition in Human Cancers

Supplementary Table 2 from FOXQ1 Regulates Epithelial-Mesenchymal Transition in Human Cancers

InTech eBooks, Apr 5, 2017

Hepatocellular carcinoma (HCC) represents 90% cases of liver cancer that is the second leading ca... more Hepatocellular carcinoma (HCC) represents 90% cases of liver cancer that is the second leading cause of cancer death in the world. With the pandemic of obesity and other metabolic syndromes in both adults and children, the incidences of fatty liver diseases and the derived HCC are on their upward track. Emerging metabolomic studies have revealed the perturbation of lipid profiles and other metabolites in fatty liver diseases and HCC. Two common metabolic features including enforced fatty acid oxidation and glycolysis could distinguish HCC from healthy liver and chronic non-tumor liver diseases. The potential translational impacts of fatty acid oxidation are gaining great interests, because many recent investigations have demonstrated that tumor cells were dependent on fatty acid oxidation for cell survival and tumor growth. Blockage of fatty acid oxidation could sensitize to metabolic stress-induced cell death and tumor growth inhibition. Thus, lipid catabolism, in terms of fatty oxidation, is tuned for tumor maintenance but vulnerable to pharmacological disruption. The therapeutic potentials of blocking fatty acid oxidation are yet to be further carefully examined.

Acta pharmacologica Sinica, Jun 15, 2020

Sorafenib is the first-line treatment of advanced hepatocellular carcinoma (HCC). However, there ... more Sorafenib is the first-line treatment of advanced hepatocellular carcinoma (HCC). However, there is a lack of validated biomarkers to predict sorafenib sensitivity. In this study we investigated the role of ACSL4, a positive-activating enzyme of ferroptosis, in sorafenib-induced cell death and HCC patient outcome. We showed that ACSL4 protein expression was negatively associated with IC 50 values of sorafenib in a panel of HCC cell lines (R = -0.952, P < 0.001). Knockdown of ACSL4 expression by specific siRNA/ sgRNA significantly attenuated sorafenib-induced lipid peroxidation and ferroptosis in Huh7 cells, and also rescued sorafenibinduced inhibition of xenograft tumor growth in vivo. We selected 29 HCC patients with surgery as primary treatment and sorafenib as postoperative adjunct therapy from a hospital-based cohort. A high proportion (66.7%) of HCC patients who had complete or partial responses to sorafenib treatment (according to the revised RECIST guideline) had higher ACSL4 expression in the pretreated HCC tissues, compared with those who had stable or progressed tumor growth (23.5%, P = 0.029). Since ACSL4 expression was independent of sorafenib treatment, it could serve as a useful predictive biomarker. Taken together, this study demonstrates that ACSL4 is essential for sorafenib-induced ferroptosis and useful for predicting sorafenib sensitivity in HCC. This study may have important translational impacts in precise treatment of HCC.

Differential regulation of histone deacetylase 1 and 2 in colorectal cancer

Proceedings of the American Association for Cancer Research Annual Meeting, Aug 20, 2003

Cell Death and Disease, Dec 13, 2012

p53 has a crucial role in governing cellular mechanisms in response to a broad range of genotoxic... more p53 has a crucial role in governing cellular mechanisms in response to a broad range of genotoxic stresses. During DNA damage, p53 can either promote cell survival by activating senescence or cell-cycle arrest and DNA repair to maintain genomic integrity for cell survival or direct cells to undergo apoptosis to eliminate extensively damaged cells. The ability of p53 to execute these two opposing cell fates depends on distinct signaling pathways downstream of p53. In this study, we showed that under DNA damage conditions induced by chemotherapeutic drugs, gamma irradiation and hydrogen peroxide, p53 upregulates a novel protein, proline-rich acidic protein 1 (PRAP1). We identified functional p53-response elements within intron 1 of PRAP1 gene and showed that these regions interact directly with p53 using ChIP assays, indicating that PRAP1 is a novel p53 target gene. The induction of PRAP1 expression by p53 may promote resistance of cancer cells to chemotherapeutic drugs such as 5-fluorouracil (5-FU), as knockdown of PRAP1 increases apoptosis in cancer cells after 5-FU treatment. PRAP1 appears to protect cells from apoptosis by inducing cell-cycle arrest, suggesting that the induction of PRAP1 expression by p53 in response to DNA-damaging agents contributes to cancer cell survival. Our findings provide a greater insight into the mechanisms underlying the pro-survival role of p53 in response to cytotoxic treatments.

Korean Journal of Medical Education, 2018

Purpose: Although medical curricula are now better structured for integration of biomedical scien... more Purpose: Although medical curricula are now better structured for integration of biomedical sciences and clinical training, most teaching and learning activities still follow the older teacher-centric discipline-specific formats. A newer pedagogical approach, known as Collaborative Learning Cases (CLCs), was adopted in the medical school to facilitate integration and collaborative learning. Before incorporating CLCs into the curriculum of year 1 students, two pilot runs using the action research method was carried out to improve the design of CLCs. Methods: We employed the four-phase Kemmis and McTaggart's action research spiral in two cycles to improve the design of CLCs. A class of 300 first-year medical students (for both cycles), 11 tutors (first cycle), and 16 tutors (second cycle) were involved in this research. Data was collected using the 5-points Likert scale survey, open-ended questionnaire, and observation. Results: From the data collected, we learned that more effort was required to train the tutors to understand the principles of CLCs and their role in the CLCs sessions. Although action research enables the faculty to improve the design of CLCs, finding the right technology tools to support collaboration and enhance learning during the CLCs remains a challenge. The two cycles of action research was effective in helping us design a better learning environment during the CLCs by clarifying tutors' roles, improving group and time management, and meaningful use of technology.

273 POSTER Candidate tumor suppessor gene DLEC1 on 3p21.3 is hypermethylated in hepatocellular carcinoma

European Journal of Cancer Supplements, 2006

Oncogene, 2011

The molecular mechanisms underlying constitutive nuclear factor-jB (NF-jB) activation in solid tu... more The molecular mechanisms underlying constitutive nuclear factor-jB (NF-jB) activation in solid tumors has not been elucidated. We show that Annexin-1 (ANXA1) is involved in this process, and suppression of ANXA1 in highly metastatic breast cancer cells impedes migration and metastasis capabilities in vitro and in vivo. ANXA1 expression correlates with NF-jB activity, suggesting that ANXA1 may be required for the constitutive activity of IjB kinase (IKK) and NF-jB in highly metatstatic breast cancer. Gel-filtration analysis demonstrated that ANXA1 co-elutes with the members of the IKK complex and NF-jB signaling pathway, and immunoprecipitation confirmed that ANXA1 can bind to and interact with IKKc or NEMO, but not IKKa or IKKb. Importantly, silencing of ANXA1 prevents the interaction of NEMO and RIP1, which indicates that ANXA1 is required for the recruitment of RIP1 to the IKK complex, which may be important for the activation of NF-jB. Downstream targets of NF-jB include uPA and CXCR4, which can be modulated by ANXA1 silencing. CXCR4-mediated migration of breast cancer cell lines in response to CXCL12 was significantly modulated by ANXA1, indicating its importance in the tissue-specific migration of breast cancer cells. Chromatin immunoprecipitation experiments confirmed that in ANXA1 overexpressed cells, NF-jB was recruited to CXCR4 promoter without external stimulation, indicating that ANXA1 is critical for the constitutive activation of NF-jB in breast cancer to promote metastasis. Finally, we show that ANXA1 overexpression enhances metastasis and reduces survival in an intracardiac metastasis model, while ANXA1deficient mice crossed with MMTV-PyMT mice display significantly less metastasis than their heterozygous littermates, indicating that ANXA1 is an important gene in breast cancer metastasis. Our data reveal that ANXA1 can constitutively activate NF-jB in breast cancer cells through the interaction with the IKK complex, and suggests that modulating ANXA1 levels has therapeutic potential to suppress breast cancer metastasis.

Neuroendocrine regulation of galanin gene expression

Galanin, 1991

Over the past several decades, we have come to appreciate the central role of intercellular commu... more Over the past several decades, we have come to appreciate the central role of intercellular communication in the regulation of normal homeostasis. Effective communication requires a dynamic web of pathways that carry precise, and informative, messages. Several classes of molecules have been shown to carry these messages, including nucleosides, amino acids, complex amines, carbohydrates, steroids, and peptides. Our understanding of the importance of small peptides in this communications network has been expanded by the physiological and pharmacological studies of numerous investigators over the past sixty years. This understanding has led to a search for additional peptide mediators to account for the exquisite subtleties of intercellular communication. Dr. Victor Mutt, whom we honor by this volume, has led the efforts to identify and characterize such peptides and is responsible for the discovery of several of the most important of them. As described elsewhere in this volume, one of the more recent products of these investigations is galanin, an amidated peptide isolated and purified from copious quantities of porcine intestinal extracts (Tatemoto et al., 1983). Amino acid sequence and structural analysis suggest that galanin is unrelated to any of the other known families of regulatory peptides, and to date it remains the only known member of its own family.

Cancers, 2020

Cytoskeletal proteins, which consist of different sub-families of proteins including microtubules... more Cytoskeletal proteins, which consist of different sub-families of proteins including microtubules, actin and intermediate filaments, are essential for survival and cellular processes in both normal as well as cancer cells. However, in cancer cells, these mechanisms can be altered to promote tumour development and progression, whereby the functions of cytoskeletal proteins are co-opted to facilitate increased migrative and invasive capabilities, proliferation, as well as resistance to cellular and environmental stresses. Herein, we discuss the cytoskeletal responses to important intracellular stresses (such as mitochondrial, endoplasmic reticulum and oxidative stresses), and delineate the consequences of these responses, including effects on oncogenic signalling. In addition, we elaborate how the cytoskeleton and its associated molecules present themselves as therapeutic targets. The potential and limitations of targeting new classes of cytoskeletal proteins are also explored, in the...

Medical Teacher, 2020

The process for introducing and developing a program for teaching medical professionalism at the ... more The process for introducing and developing a program for teaching medical professionalism at the National University of Singapore, School of Medicine is outlined. Professionalism was recognised as embracing 'honesty and integrity,' 'responsibility and participation,' 'respect and sensitivity,' and 'compassion and empathy.' Those broad values are expressed as specific attitudes and behaviours that are taught and assessed throughout the course. Honesty and integrity, for example, are demonstrated by 'presenting original, authentic assignments' (in medical education); and 'accepting personal mistakes and honestly acknowledging them' (in clinical training and practice). Values and items of behaviour were drawn from the literature, and reviewed and refined to address needs identified within the Medical School. A broad spectrum of pre-clinical and clinical teachers contributed to this development. The program was reassessed to determine the extent to which it has been implemented and has evolved following its adoption. The results are confirming in that: the majority of recommendations have been implemented; the program has developed further; and is supported by ancillary student enrichment activities. Medical professionalism has been given prominence through all phases of the course. Nevertheless, challenges remain and particularly in the extent to which medical professionalism is taught and assessed in various clinical postings.

Biochemical and Biophysical Research Communications, 2019

Background: CCAAT enhancer binding protein a (C/EBPa), as an important transcription factor invol... more Background: CCAAT enhancer binding protein a (C/EBPa), as an important transcription factor involved in cell proliferation, differentiation and metabolism, was up-regulated in primary hepatocellular carcinoma (HCC) and predicted poorer prognosis. In this study, we explored how histone deacetylases (HDACs) up-regulated C/EBPa in HCC. Methods: The protein expressions of HDAC1, HDAC2 were associated with C/EBPa by immunohistochemistry staining in a HCC tissue microarray. HCC cells were then treated with HDAC inhibitors or siRNAs to determine the roles of miR-124-3p and miR-25 in the regulation of C/EBPa mRNA expression. Results: Both HDAC1 and HDAC2 proteins were significantly associated with C/EBPa. Inhibition of HDAC by either pharmacological inhibitors or siRNAs decreased C/EBPa mRNA expression in dose-dependent manners in HCC cells. HDAC inhibitors reduced C/EBPa mRNA stability as shown by pmiRGLO luciferase reporter assays. HDAC inhibition consistently induced miR-124-3p and miR-25 expression. Conversely, blockage of miR-124-3p and/or miR-25 by treatment with specific synthetic inhibitors abolished C/EBPa reduction. More importantly, C/EBPa mRNA stability could be rescued by site-directed mutations of miR-124-3p or miR-25 recognition sites in the C/EBPa 3 0 UTR sequence. In summary, HDAC may up-regulate C/EBPa expression through miR-124-3p and miR-25 in HCC.

Cytotechnology, 2019

The tumor suppressor DLEC1 has been shown to promote cell proliferation when AP-2a2 is down-regul... more The tumor suppressor DLEC1 has been shown to promote cell proliferation when AP-2a2 is down-regulated in HCT116 stable clones, suggesting its pro-survival nature. However, the pro-survival function of DLEC1 has not been confirmed in other cells and its underlying mechanisms remain elusive. Therefore, we knocked down DLEC1 in a panel of cell lines and found that DLEC1 depletion caused various extents of cell death through intrinsic pathway. DLEC1 overexpression promoted cell survival and reduced cell death in cancer cells after 5-FU treatment, while DLEC1 down-regulation sensitized cancer cells to 5-FU. Further studies demonstrated that DLEC1 attenuated the increase in cleaved PARP, caspase-3 and caspase-7, the activity of caspase-9 and the diffusion of cytosolic cytochrome c from mitochondria. Our data also showed that BCL-XL was up-regulated by DLEC1 in stable clones after 5-FU treatment. Altogether, these results indicated that DLEC1 protects cells against cell death induced by 5-FU through the attenuation of active proteins in caspase cascade and the up-regulation of BCL-XL. Therefore, DLEC1 can be a pro-survival protein under certain circumstances and a potential therapeutic target for increasing sensitivity of cancer cells to 5-FU.

Ribosomal protein L7a gene is up-regulated but not fused to the tyrosine kinase receptor as chimeric trk oncogene in human colorectal carcinoma

International Journal of Oncology, 2000

Ribosomal protein L7a (rp L7a) was identified in a subtractive hybridization screen as a gene up-... more Ribosomal protein L7a (rp L7a) was identified in a subtractive hybridization screen as a gene up-regulated in human colorectal cancer. Expression of rp L7a was greater than 2-fold higher in tumors compared to adjacent normal mucosa in 72% of the patients studied (n=36). rp L7a was also up-regulated in concomitant polyps. The number of patients with rp L7a T/N ratio of >2 was significantly higher in the female (16/18) than in the male (10/18). rp L7a expression was also significantly higher in females with lymph node involvement compared to males. These results indicate that rp L7a expression is related to tumor growth in colorectal cancer especially in females, where it may also be related to tumor spread. There was no correlation of rp L7a expression with tumor cell differentiation. We also show that rp L7a does not exist as a fusion oncogene (trk-2h) in colorectal cancer.