Wan-Chun Li - Academia.edu (original) (raw)

Papers by Wan-Chun Li

Cell Death & Disease

Mitochondrial transcriptional factor A (TFAM) acts as a key regulatory to control mitochondrial D... more Mitochondrial transcriptional factor A (TFAM) acts as a key regulatory to control mitochondrial DNA (mtDNA); the impact of TFAM and mtDNA in modulating carcinogenesis is controversial. Current study aims to define TFAM mediated regulations in head and neck cancer (HNC). Multifaceted analyses in HNC cells genetically manipulated for TFAM were performed. Clinical associations of TFAM and mtDNA encoded Electron Transport Chain (ETC) genes in regulating HNC tumourigenesis were also examined in HNC specimens. At cellular level, TFAM silencing led to an enhanced cell growth, motility and chemoresistance whereas enforced TFAM expression significantly reversed these phenotypic changes. These TFAM mediated cellular changes resulted from (1) metabolic reprogramming by directing metabolism towards aerobic glycolysis, based on the detection of less respiratory capacity in accompany with greater lactate production; and/or (2) enhanced ERK1/2-Akt-mTORC-S6 signalling activity in response to TFAM i...

Diagnostics

Oral cancer is one of the most common head and neck malignancies and has an overall 5-year surviv... more Oral cancer is one of the most common head and neck malignancies and has an overall 5-year survival rate that remains below 50%. Oral cancer is generally preceded by oral potentially malignant disorders (OPMDs) but determining the risk of OPMD progressing to cancer remains a difficult task. Several diagnostic technologies have been developed to facilitate the detection of OPMD and oral cancer, and some of these have been translated into regulatory-approved in vitro diagnostic systems or medical devices. Furthermore, the rapid development of novel biomarkers, electronic systems, and artificial intelligence may help to develop a new era where OPMD and oral cancer are detected at an early stage. To date, a visual oral examination remains the routine first-line method of identifying oral lesions; however, this method has certain limitations and as a result, patients are either diagnosed when their cancer reaches a severe stage or a high-risk patient with OPMD is misdiagnosed and left un...

Biomolecules

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. I... more Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. It is well recognized that environmental challenges such as smoking, viral infection and alcohol consumption are key factors underlying HNSCC pathogenesis. Other than major clinical interventions (e.g., surgical resection, chemical and radiotherapy) that have been routinely practiced over years, adjuvant anticancer agents from Traditional Herbal Medicine (THM) are proposed, either alone or together with conventional therapies, to be experimentally effective for improving treatment efficacy in different cancers including HNSCCs. At a cellular and molecular basis, THM extracts could modulate different malignant indices via distinct signaling pathways and provide better control in HNSCC malignancy and its clinical complications such as radiotherapy-induced xerostomia/oral mucositis. In this article, we aim to systemically review the impacts of THM in regulating HNSCC tumorous identities and ...

Frontiers in Oncology

To support great demand of cell growth, cancer cells preferentially obtain energy and biomacromol... more To support great demand of cell growth, cancer cells preferentially obtain energy and biomacromolecules by glycolysis over mitochondrial oxidative phosphorylation (OxPhos). Among all glycolytic enzymes, hexokinase (HK), a rate-limiting enzyme at the first step of glycolysis to catalyze cellular glucose into glucose-6-phosphate, is herein emphasized. Four HK isoforms, HK1-HK4, were discovered in nature. It was shown that HK2 expression is enriched in many tumor cells and correlated with poorer survival rates in most neoplastic cells. HK2-mediated regulations for cell malignancy and mechanistic cues in regulating head and neck tumorigenesis, however, are not fully elucidated. Cellular malignancy index, such as cell growth, cellular motility, and treatment sensitivity, and molecular alterations were determined in HK2-deficient head and neck squamous cell carcinoma (HNSCC) cells. By using various cancer databases, HK2, but not HK1, positively correlates with HNSCC progression in a stage-dependent manner. A high HK2 expression was detected in head and neck cancerous tissues compared with their normal counterparts, both in mouse and human subjects. Loss of HK2 in HNSCC cells resulted in reduced cell (in vitro) and tumor (in vivo) growth, as well as decreased epithelial-mesenchymal transition-mediated cell movement; in contrast, HK2-deficient HNSCC cells exhibited greater sensitivity to chemotherapeutic drugs cisplatin and 5-fluorouracil but are more resistant to photodynamic therapy, indicating that HK2 expression could selectively define treatment sensitivity in HNSCC cells. At the molecular level, it was found that HK2 alteration drove metabolic reprogramming toward OxPhos and modulated oncogenic Akt and mutant TP53-mediated signals in HNSCC cells. In summary, the present study showed that HK2 suppression could lessen HNSCC oncogenicity and modulate therapeutic sensitivity, thereby being an ideal therapeutic target for HNSCCs.

Journal of Virology

Kaposi's sarcoma associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma... more Kaposi's sarcoma associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an acquired immunodeficiency syndrome (AIDS)-defining cancer with abnormal angiogenesis. The high incidence of KS in human immunodeficiency viruses (HIV)-infected AIDS patients has been ascribed to HIV-1 and KSHV interaction, focusing on secretory proteins. HIV-1 secreted protein HIV-Tat has been found to synergize with KSHV lytic proteins to induce angiogenesis. However, the impact and underlying mechanisms of HIV-Tat in KSHV-infected endothelial cells undergoing viral lytic reactivation remain unclear. Here, we identified LINC00313 as a novel KSHV reactivation-activated long non-coding RNA (lncRNA) that interacts with HIV-Tat. We found that LINC00313 overexpression inhibits cell migration, invasion and tube formation, and this suppressive effect was relieve by HIV-Tat. In addition, LINC00313 bound to polycomb repressive complex 2 (PRC2) complex components and this interaction wa...

Clinical Oral Investigations

International Journal of Molecular Sciences

Considering the great energy and biomass demand for cell survival, cancer cells exhibit unique me... more Considering the great energy and biomass demand for cell survival, cancer cells exhibit unique metabolic signatures compared to normal cells. Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. Recent findings have shown that environmental challenges, as well as intrinsic metabolic manipulations, could modulate HNSCC experimentally and serve as clinic prognostic indicators, suggesting that a better understanding of dynamic metabolic changes during HNSCC development could be of great benefit for developing adjuvant anti-cancer schemes other than conventional therapies. However, the following questions are still poorly understood: (i) how does metabolic reprogramming occur during HNSCC development? (ii) how does the tumorous milieu contribute to HNSCC tumourigenesis? and (iii) at the molecular level, how do various metabolic cues interact with each other to control the oncogenicity and therapeutic sensitivity of HNSCC? In this review article...

Scientific Reports

Ductal epithelium is primarily detected in porcine neonatal pancreatic cell clusters (NPCCs) bear... more Ductal epithelium is primarily detected in porcine neonatal pancreatic cell clusters (NPCCs) bearing grafts, suggesting that transplants might exhibit progenitor-like phenotypes. Here we found that soon after NPCC isolation, PDX1 + /insulin − and SOX9 + pancreatic progenitor-like cells dramatically increased while dual-hormonal progenitor-like cells were routinely observed in NPCC culture. After transplantation (Tx), insulin + cells increased and PDX1 + and SOX9 + cells gradually decreased in both non-diabetic (NDM) and streptozotocin-induced diabetic (DM) grafts over 2 months. Strikingly, a significantly higher percentage of insulin + cells were detected in 9-day and 16-day, but not in 23-day, 30-day and 60-day grafts implying that hyperglycemia could only facilitate NPCC-derived β cells early post-Tx. A higher percentage of NPCC-derived β cells in early DM grafts was determined via an enhanced neogenic differentiation based on the detection of insulin + cells budding out from PDX1 + / SOX9 + epithelium. Interestingly, a drop in SOX9 + progenitor-like cells was detected 16 days post-Tx in DM grafts whilst PDX1 + cells do not show a significant difference until 60 days post-Tx between DM and NDM grafts, demonstrating that distinct progenitor-like populations fuel new β cells post-Tx. In conclusion, PDX1 + /SOX9 + cells could be quickly activated after NPCC isolation, maintain their multipotency in culture and differentiate into new β cell post-Tx.

Journal of Oral & Facial Pain and Headache

Aims: To elucidate the role of Link N in regulating inflammatory molecules from human mesenchymal... more Aims: To elucidate the role of Link N in regulating inflammatory molecules from human mesenchymal stem cells (hMSCs) under interleukin (IL)-1β stimulation in vitro and under Complete Freund's Adjuvant (CFA)-induced arthritis of the temporomandibular joint (TMJ) in vivo. Methods: In vitro analysis of inflammatory cytokines and epithelial-mesenchymal transition (EMT) genes in hMSCs treated with Link N, IL-1β, and co-stimulation of IL-1β and Link N was undertaken using Luminex multiplex assays and real-time polymerase chain reaction, respectively. To determine the impact of Link N in ameliorating TMJ tissue homeostasis in arthritic conditions, histologic changes in CFA-induced arthritic TMJ tissues followed by application of Link N were examined. All data were analyzed using one-way analysis of variance with Bonferroni post hoc test. Results: Increased levels of IL-6; interferon gamma-inducible protein-10; and regulated upon activation, normal T cell expressed, and secreted (RANTES) were detected in response to IL-1β treatment, but these levels were significantly decreased in the co-stimulation group. In contrast, secreted IL-4, IL-10, and transforming growth factor β1-β3 proteins, as well as intracellular erb-b2 receptor tyrosine kinase 3 and Nodal homolog genes, were increased significantly in the co-stimulation group compared to the IL-1β group. Histologic analysis showed significant recovery for rat condyle thickness in the Link N-treated group when compared to the CFA-induced arthritis group. Conclusion: These findings indicate that Link N could modulate inflammation and EMT in vitro and repair arthritis-mediated TMJ disruption in vivo. Link N could be a potential therapeutic agent for TMJ disorder patients.

Stem cell reports, Jan 15, 2018

Pancreatic duct epithelial cells have been suggested as a source of progenitors for pancreatic gr... more Pancreatic duct epithelial cells have been suggested as a source of progenitors for pancreatic growth and regeneration. However, genetic lineage-tracing experiments with pancreatic duct-specific Cre expression have given conflicting results. Using immunofluorescence and flow cytometry, we show heterogeneous expression of both HNF1β and SOX9 in adult human and murine ductal epithelium. Their expression was dynamic and diminished significantly after induced replication. Purified pancreatic duct cells formed organoid structures in 3D culture, and heterogeneity of expression of Hnf1β and Sox9 was maintained even after passaging. Using antibodies against a second cell surface molecule CD51 (human) or CD24 (mouse), we could isolate living subpopulations of duct cells enriched for high or low expression of HNF1β and SOX9. Only the CD24(Hnfβ/Sox9) subpopulation was able to form organoids.

Journal of the Formosan Medical Association = Taiwan yi zhi, Jan 18, 2017

Bioaggregates such as Portland cement (PC) can be an economical alternative for mineral trioxide ... more Bioaggregates such as Portland cement (PC) can be an economical alternative for mineral trioxide aggregate (MTA) with additional benefit of less discoloration. MTA has been known to induce differentiations of several dental cells. MicroRNAs are important regulators of biological processes, including differentiation, physiologic homeostasis, and disease progression. This study is to explore how PC enhances the differentiation of periodontal ligament (PDL) cells in microRNAs level. PDL cells were cultured in a regular PC- or MTA-conditioned medium or an osteoinduction medium (OIM). Alizarin red staining was used to evaluate the extent of mineralization. Transfection of microRNA mimics induced exogenous miR-31 and miR-146a expression. The expression of microRNAs and differentiation markers was assayed using reverse-transcriptase polymerase chain reaction. PC enhanced the mineralization of PDL cells in a dose-dependent manner in the OIM. Exogenous miR-31 and miR-146a expression upregula...

International journal of medical sciences, 2016

Diabetic nephropathy (DN) is a major leading cause of kidney failure. Recent studies showed that ... more Diabetic nephropathy (DN) is a major leading cause of kidney failure. Recent studies showed that serological microRNAs (miRs) could be utilized as biomarkers to identify disease pathogenesis; the DN-related miRs, however, remained to be explored. A prospective case-control study was conducted. The clinical significance of five potential miRs (miR-21, miR-29a, miR-29b, miR-29c and miR192) in type 2 Diabetes Mellitus (T2DM) patients who have existing diabetic retinopathy with differential Albumin:Creatinine Ratio (ACR) and estimated Glomerular Filtration Rate (eGFR) was performed using quantitative RT-PCR analysis. The subjects with diabetic retinopathy enrolled in Taipei City Hospital, Taiwan, were classified into groups of normal albuminuria (ACR<30mg/g; N=12); microalbuminuria (30mg/g<ACR<300mg/g; N=17) and overt proteinuria (ACR>300mg/g; N=21) as well as 18 low-eGFR (eGFR<60ml/min) and 32 high-eGFR (eGFR>60ml/min). The level of serum miRs was statistically correl...

Journal of gastroenterology and hepatology, Jan 24, 2016

In view of its unique properties of detoxification and involvement of metabolic and biochemical f... more In view of its unique properties of detoxification and involvement of metabolic and biochemical functions, in vitro hepatocyte culture serves as a valuable material for drug screening and mechanistic analysis for pathology of liver diseases. The restriction of rapid de-differentiation and inaccessibility of human hepatocytes from routine clinical procedure, however, limits its use. To address this issue, the effort to direct human mesenchymal stem cells (hMSCs) into hepatocytes using a modified protocol was proposed. With the additional treatment of Histone deacetylase inhibitor (HDACi) and DNA methyltransferase inhibitor (DNMTi), in vitro hMSC-derived hepatocytes were cultivated and their hepatic characteristics were examined. By using a modified protocol, it was shown that Trichostatin A (TSA) and 5-Aza-2-deoxycitidine (5-Aza) protected differentiating cells from death and could sufficiently trigger a wide range of liver-specific markers as well as liver functions including albumi...

Oncotarget, Jan 24, 2016

Curative surgical resection (CSR) remains the most effective therapeutic intervention for patient... more Curative surgical resection (CSR) remains the most effective therapeutic intervention for patients with hepatocellular carcinoma (HCC); however, frequent post-surgical recurrence leads to high cancer related mortality. This study aimed to clarify the role of body mass index (BMI) and serum cholesterol level in predicting post-surgical outcomes in HCC patients after CSR. A total of 484 HCC patients including 213 BMIhigh and 271 BMIlow patients were included. Overall survival (OS) and recurrence-free survival (RFS) rates were examined in patients with differential BMI and serum cholesterol level. The analysis showed that significant different 1-, 3- and 5-year cumulative OS rates (P-value=0.015) and RFS rate (P-value=0.010) between BMIlow and BMIhigh patients. Further analysis in groups with differential serum cholesterol levels among BMIlow and BMIhigh patients indicated that the BMIlow/Chollow patients exhibited the significant lower cumulative OS and RFS rates in comparison with th...

Oncotarget, 2014

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. W... more Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. While numerous potent dietary insults were considered as oncogenic players for HNSCC development, the impact of metabolic imbalance was less emphasized during HNSCC carcinogenesis. Previous preclinical and epidemiological investigations showed that DM could possibly be correlated with greater incidence and poorer prognosis in HNSCC patients; however, the outcomes from different groups are contradictive and underlying mechanisms remains elusive. In the present study, the changes of cellular malignancy in response to prolonged glucose incubation in HNSCC cells were examined. The results demonstrated that hyperglycemia enhanced HNSCC cell malignancy over time through suppression of cell differentiation, promotion of cell motility, increased resistance to cisplatin, and up-regulation of the nutrient-sensing Akt/AMPK-mTORC1 pathway. Further analysis showed that a more aggressive tongue neoplastic progression was found under DM conditions compared to non-DM state whereas DM pathology led to a higher percentage of cervical lymph node metastasis and poorer prognosis in HNSCC patients. Taken together, the present study confirms that hyperglycemia and DM could enhance HNSCC malignancy and the outcomes are of great benefit in providing better anti-cancer treatment strategy for DM patients with HNSCC.

Methods in molecular biology (Clifton, N.J.), 2009

Transdifferentiation is defined as an irreversible switch in postnatal life of one differentiated... more Transdifferentiation is defined as an irreversible switch in postnatal life of one differentiated cell to another. Transdifferentiation from different cellular origins into pancreatic-like beta-cells is of clinical significance since this approach may offer a potential cure for diabetes. In order to achieve this goal, the liver is considered as a suitable candidate due to its close developmental relationship to the pancreas, its large size and a well-documented regenerative capacity that could provide enough original tissues to initiate the transdifferentiation procedure. In this chapter, we describe a protocol to overexpress Pdx1, a master regulator essential for pancreas development in the cultured human liver cell line, HepG2.

Journal of the Chinese Medical Association : JCMA, 2014

A recent research breakthrough has demonstrated that the ectopic expression of four genes is suff... more A recent research breakthrough has demonstrated that the ectopic expression of four genes is sufficient to reprogram human fibroblasts into inducible pluripotent stem cells (iPSCs). However, whether human dental pulp cells (DPCs) could be reprogrammed into iPSCs remains an open question. In this study, we demonstrated that DPCs from deciduous and permanent teeth can be reprogrammed into iPSCs without c-Myc and had the capacity to differentiate into neuron-like cells. DPCs were obtained from donors and reprogrammed into iPSCs using retroviral transduction with SOX2, OCT4, and KLF4. Then, these iPSCs were differentiated into neuron-like cells. Microarray and bioinformatics were used to compare the gene expression profile among these iPSCs and iPSC-derived neuron-like cells. The DPCs displayed a high vitality and capability to quickly restart proliferation and expressed elevated pluripotency similar to mesenchymal stem cells. According to our results, DPC-derived iPSC colonies that cou...

Journal of Endodontics, 2012

MicroRNAs are small noncoding RNAs that play crucial roles in regulating normal and pathologic fu... more MicroRNAs are small noncoding RNAs that play crucial roles in regulating normal and pathologic functions. Bacterial lipopolysaccharide (LPS) is one of the key regulators of pulpal pathogenesis. This study investigated how LPS regulates microRNA expression and affects the phenotype of human dental pulp cells (DPCs). Primary DPCs were established and immortalized to achieve immortalized DPCs (I-DPCs). DPCs and I-DPCs were treated with LPS and examined to identify changes in microRNA expression, cell proliferation, and cell migration. Quantitative reverse-transcriptase polymerase chain reaction was used to detect changes in gene expression. Exogenous miR-146a expression was performed transfection with pre-mir-146a mimic. Knockdown of interleukin receptor-associated kinase (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) expression was performed by small interference oligonucleotide transfection. Western blot analysis was used to detect changes in the expression of the IRAK1 and TRAF6 proteins. The differentiation of DPCs was induced by osteogenic medium. I-DPCs had a higher level of human telomerase reverse transcriptase gene than the parental DPCs. Up-regulation of miR-146a expression and an increase in migration was induced by LPS treatment of DPCs and I-DPCs. Exogenous miR-146a expression increased the migration of DPCs and I-DPCs and down-regulated the expression of IRAK1 and TRAF6. Knockdown of IRAK1 and/or TRAF6 increased the migration of DPCs. The results suggested that LPS is able to increase the migration of DPCs by modulating the miR-146a-TRAF6/IRAK1 regulatory cascade.

Journal of the Chinese Medical Association : JCMA, Jan 16, 2014

Diabetes mellitus (DM) is a global health care issue resulting from hyperglycemia-mediated life-t... more Diabetes mellitus (DM) is a global health care issue resulting from hyperglycemia-mediated life-threatening complications. Although the use of glucose-lowering agents is routinely practiced, high dependence on medication leads to poor quality of life for DM patients. While it is still not feasible to precisely determine the critical timing when DM is truly established, perhaps the best way to reduce DM-associated mortality is to prevent it. To this end, an exploration of prognostic molecules sensitive enough to detect early physiological alteration at the initiating stage would be required. Recently discovered small noncoding molecules, microRNAs (miRs), in body fluid seem promising to be utilized as a biomarker to monitor DM initiation and progression, as it is believed that expression of circulating miRs reflects disease pathology. Current DM-related miRs were often referred to miRs differentially expressed in insulin target organs (liver, muscle, and adipose tissues) or circulati...