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FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells

Hung TH, Chen CM, Tseng CP, Shen CJ, Wang HL, Choo KB, et al.

Int J Biochem Cell Biol, 2014 Aug;53:55-65.
PMID: 24814288 DOI: 10.1016/j.biocel.2014.04.011

Multidrug-resistant (MDR) cancer is a major clinical problem in chemotherapy of cancer patients. We have noted inappropriate PKCδ hypomethylation and overexpression of genes in the PKCδ/AP-1 pathway in the human uterus sarcoma drug-resistant cell line, MES-SA/Dx5 cells, which also overexpress p-glycoprotein (ABCB1). Recent studies have indicated that FZD1 is overexpressed in both multidrug-resistant cancer cell lines and in clinical tumor samples. These data have led us to hypothesize that the FZD1-mediated PKCδ signal-transduction pathway may play an important role in drug resistance in MES-SA/Dx5 cells. In this work, the PKCδ inhibitor Rottlerin was found to reduce ABCB1 expression and to inhibit the MDR drug pumping ability in the MES-SA/Dx5 cells when compared with the doxorubicin-sensitive parental cell line, MES-SA. PKCδ was up-regulated with concurrent up-regulation of the mRNA levels of the AP-1-related factors, c-JUN and c-FOS. Activation of AP-1 also correlated with up-regulation of the AP-1 downstream genes HGF and EGR1. Furthermore, AP-1 activities were reduced and the AP-1 downstream genes were down-regulated in Rottlerin-treated or PKCδ shRNA-transfected cells. MES-SA/Dx5 cells were resensitized to doxorubicin-induced toxicity by co-treatment with doxorubicin and Rottlerin or PKCδ shRNA. In addition, cell viability and drug pump-out ability were significantly reduced in the FZD1 inhibitor curcumin-treated and FZD1 shRNA-knockdown MES-SA/Dx5 cells, indicating involvement of PKCδ in FZD1-modulated ABCB1 expression pathway. Taken together, our data demonstrate that FZD1 regulates PKCδ, and the PKCδ/AP-1 signalling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells.
Long-term outcome of native tissue reconstructive vaginal surgery for advanced pelvic organ prolapse at 86 months: Hysterectomy versus hysteropexy

Lo TS, Pue LB, Hung TH, Wu PY, Tan YL

J Obstet Gynaecol Res, 2015 Jul;41(7):1099-107.
PMID: 25808989 DOI: 10.1111/jog.12678

To evaluate and compare the long-term outcome of sacrospinous ligament fixation (SSF) in combination with various other compartment defect native tissue repairs with hysterectomy or hysteropexy.
Fulltext A novel de novo mutation in COL2A1 gene associated with fetal skeletal dysplasia

Chu FC, Hii LY, Hung TH, Lo LM, Hsieh TT, Shaw SW

Taiwan J Obstet Gynecol, 2021 Mar;60(2):359-362.
PMID: 33678343 DOI: 10.1016/j.tjog.2021.01.017

OBJECTIVE: Skeletal dysplasias, caused by genetic mutations, are a heterogenous group of heritable disorders affecting bone development during fetal life. Stickler syndrome, one of the skeletal dysplasias, is an autosomal dominant connective tissue disorder caused by abnormal collagen synthesis owing to a genetic mutation in COL2A1.
CASE REPORT: We present the case of a 38-year-old multipara woman whose first trimester screening showed a normal karyotype. However, the bilateral femur and humerus length symmetrically shortened after 20 weeks. Next-generation sequencing for mutations in potential genes leading to skeletal dysplasia detected a novel de novo mutation (c.1438G > A, p.Gly480Arg) in COL2A1, causing Stickler syndrome type 1. This pathogenic mutation might impair or destabilize the collagen structure, leading to collagen type II, IX, and XI dysfunction.
CONCLUSION: We identified a novel de novo mutation in COL2A1 related to the STL1 syndrome and delineated the extent of the skeletal dysplasia disease spectrum.
Fulltext Risk factors and adverse maternal and perinatal outcomes for women with dichorionic twin pregnancies complicated by gestational diabetes mellitus: A retrospective cross-sectional study

Hung TH, Hsieh TT, Shaw SW, Kok Seong C, Chen SF

J Diabetes Investig, 2021 Jun;12(6):1083-1091.
PMID: 33064935 DOI: 10.1111/jdi.13441

AIMS/INTRODUCTION: The association between gestational diabetes mellitus (GDM) and adverse maternal and perinatal outcomes in twin pregnancies remains unclear. This study was undertaken to highlight risk factors for GDM in women with dichorionic (DC) twins, and to determine the association between GDM DC twins and adverse maternal and perinatal outcomes in a large homogeneous Taiwanese population.
MATERIALS AND METHODS: A retrospective cross-sectional study was carried out on 645 women with DC twins, excluding pregnancies complicated by one or both fetuses with demise (n = 22) or congenital anomalies (n = 9), who gave birth after 28 complete gestational weeks between 1 January 2001 and 31 December 2018. Univariable and multiple logistic regression analyses were carried out.
RESULTS: Maternal age >34 years (adjusted odds ratio 2.52; 95% confidence interval 1.25-5.07) and pre-pregnancy body mass index >24.9 kg/m2 (adjusted odds ratio 2.83, 95% confidence interval 1.47-5.46) were independent risk factors for GDM in women with DC twins. Newborns from women with GDM DC twins were more likely to be admitted to the neonatal intensive care unit (adjusted odds ratio 1.70, 95% confidence interval 1.06-2.72) than newborns from women with non-GDM DC twins. Other pregnancy and neonatal outcomes were similar between the two groups.
CONCLUSIONS: Advanced maternal age and pre-pregnancy overweight or obesity are risk factors for GDM in women with DC twins. Except for a nearly twofold increased risk of neonatal intensive care unit admission of newborns, the pregnancy and neonatal outcomes for women with GDM DC twins are similar to those for women with non-GDM DC twins.
Fulltext Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis

Lan YW, Choo KB, Chen CM, Hung TH, Chen YB, Hsieh CH, et al.

Stem Cell Res Ther, 2015;6:97.
PMID: 25986930 DOI: 10.1186/s13287-015-0081-6

Idiopathic pulmonary fibrosis is a progressive diffuse parenchymal lung disorder of unknown etiology. Mesenchymal stem cell (MSC)-based therapy is a novel approach with great therapeutic potential for the treatment of lung diseases. Despite demonstration of MSC grafting, the populations of engrafted MSCs have been shown to decrease dramatically 24 hours post-transplantation due to exposure to harsh microenvironments. Hypoxia is known to induce expression of cytoprotective genes and also secretion of anti-inflammatory, anti-apoptotic and anti-fibrotic factors. Hypoxic preconditioning is thought to enhance the therapeutic potency and duration of survival of engrafted MSCs. In this work, we aimed to prolong the duration of survival of engrafted MSCs and to enhance the effectiveness of idiopathic pulmonary fibrosis transplantation therapy by the use of hypoxia-preconditioned MSCs.
Fulltext Physiological responses of rosewoods Dalbergia cochinchinensis and D. oliveri under drought and heat stresses

Hung TH, Gooda R, Rizzuto G, So T, Thammavong B, Tran HT, et al.

Ecol Evol, 2020 Oct;10(19):10872-10885.
PMID: 33072302 DOI: 10.1002/ece3.6744

Dalbergia cochinchinensis and D. oliveri are classified as vulnerable and endangered, respectively, in the IUCN Red List and under continued threat from deforestation and illegal harvesting for rosewood. Despite emerging efforts to conserve and restore these species, little is known of their responses to drought and heat stress, which are expected to increase in the Greater Mekong Subregion where the species co-occur and are endemic. In this study of isolated and combined drought and heat effects, we found that D. oliveri had an earlier stomatal closure and more constant midday water potential in response to increasing drought level, suggesting that D. oliveri is relatively isohydric while D. cochinchinensis is relatively anisohydric. Heat shock and drought had synergistic effects on stomatal closure. Our results indicate contrasting relationships in water relations, photosynthetic pigment levels, and total soluble sugars. An increase in chlorophyll a was observed in D. cochinchinensis during drought, and a concomitant increase in carotenoid content likely afforded protection against photo-oxidation. These physiological changes correlated with higher total soluble sugars in D. cochinchinensis. By contrast, D. oliveri avoided drought by reducing chlorophyll content and compromising productivity. Anisohydry and drought tolerance in D. cochinchinensis are adaptations which fit well with its ecological niche as a pioneering species with faster growth in young trees. We believe this understanding of the stress responses of both species will be crucial to their effective regeneration and conservation in degraded habitats and in the face of climate change.
Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway

Hung TH, Hsu SC, Cheng CY, Choo KB, Tseng CP, Chen TC, et al.

Oncotarget, 2014 Dec 15;5(23):12273-90.
PMID: 25401518

Multidrug resistance in cancer cells arises from altered drug permeability of the cell. We previously reported activation of the Wnt pathway in ABCB1-overexpressed human uterus sarcoma drug-resistant MES-SA/Dx5 cells through active β-catenin and associated transactivation activities, and upregulation of Wnt-targeting genes. In this study, Wnt5A was found to be significantly upregulated in MES-SA/Dx5 and MCF7/ADR2 cells, suggesting an important role for the Wnt5A signaling pathway in cancer drug resistance. Higher cAMP response elements and Tcf/Lef transcription activities were shown in the drug-resistant cancer cells. However, expression of Wnt target genes and CRE activities was downregulated in Wnt5A shRNA stably-transfected MES-SA/Dx5 cells. Cell viability of the drug-resistant cancer cells was also reduced by doxorubicin treatment and Wnt5A shRNA transfection, or by Wnt5A depletion. The in vitro data were supported by immunohistochemical analysis of 24 paired breast cancer biopsies obtained pre- and post-chemotherapeutic treatment. Wnt5A, VEGF and/or ABCB1 were significantly overexpressed after treatment, consistent with clinical chemoresistance. Taken together, the Wnt5A signaling pathway was shown to contribute to regulating the drug-resistance protein ABCB1 and β-catenin-related genes in antagonizing the toxic effects of doxorubicin in the MDR cell lines and in clinical breast cancer samples.
Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines

Hung TH, Li YH, Tseng CP, Lan YW, Hsu SC, Chen YH, et al.

Cancer Gene Ther, 2015 May;22(5):262-70.
PMID: 25908454 DOI: 10.1038/cgt.2015.15

Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Inhibition of c-MET signaling induces apoptosis in a variety of cancers. It has also been recognized as a novel anticancer therapy approach. Furthermore, reports have also indicated that constitutive expression of P-glycoprotein (ABCB1) is involved in the HGF/c-MET-related pathway of multidrug resistance ABCB1-positive human hepatocellular carcinoma cell lines. We previously reported that elevated expression levels of PKCδ and AP-1 downstream genes, and HGF receptor (c-MET) and ABCB1, in the drug-resistant MES-SA/Dx5 cells. Moreover, leukemia cell lines overexpressing ABCB1 have also been shown to be more resistant to the tyrosine kinase inhibitor imatinib mesylate. These findings suggest that chemoresistant cancer cells may also develop a similar mechanism against chemotherapy agents. To circumvent clinical complications arising from drug resistance during cancer therapy, the present study was designed to investigate apoptosis induction in ABCB1-overexpressed cancer cells using c-MET-targeted RNA interference technology in vitro and in vivo. The results showed that cell viability decreased and apoptosis rate increased in c-MET shRNA-transfected HGF/c-MET pathway-positive MES-SA/Dx5 and MCF-7/ADR2 cell lines in a dose-dependent manner. In vivo reduction of tumor volume in mice harboring c-MET shRNA-knockdown MES-SA/Dx5 cells was clearly demonstrated. Our study demonstrated that downregulation of c-MET by shRNA-induced apoptosis in a multidrug resistance cell line.
Fulltext Range-wide differential adaptation and genomic offset in critically endangered Asian rosewoods

Hung TH, So T, Thammavong B, Chamchumroon V, Theilade I, Phourin C, et al.

Proc Natl Acad Sci U S A, 2023 Aug 15;120(33):e2301603120.
PMID: 37549265 DOI: 10.1073/pnas.2301603120

In the billion-dollar global illegal wildlife trade, rosewoods have been the world's most trafficked wild product since 2005. Dalbergia cochinchinensis and Dalbergia oliveri are the most sought-after rosewoods in the Greater Mekong Subregion. They are exposed to significant genetic risks and the lack of knowledge on their adaptability limits the effectiveness of conservation efforts. Here, we present genome assemblies and range-wide genomic scans of adaptive variation, together with predictions of genomic offset to climate change. Adaptive genomic variation was differentially associated with temperature and precipitation-related variables between the species, although their natural ranges overlap. The findings are consistent with differences in pioneering ability and in drought tolerance. We predict their genomic offsets will increase over time and with increasing carbon emission pathway but at a faster pace in D. cochinchinensis than in D. oliveri. These results and the distinct gene-environment association in the eastern coastal edge of Vietnam suggest species-specific conservation actions: germplasm representation across the range in D. cochinchinensis and focused on hotspots of genomic offset in D. oliveri. We translated our genomic models into a seed source matching application, seedeR, to rapidly inform restoration efforts. Our ecological genomic research uncovering contrasting selection forces acting in sympatric rosewoods is of relevance to conserving tropical trees globally and combating risks from climate change.