المؤلفون: Wen-Der Lin, Chia-Hao Chang, Jhih-Kai Pan, Forn-Chia Lin, Yu-Chia Chen, Ya-Jyun Chen, Po-Shun Wang, Wei-Qiao Hong, Sheng-Yuan Chen, Cheng-Han Lin, Yao-Lung Kuo, Wei-Pang Chung, Hui-Chuan Cheng, Michael Hsiao, Chia-Ning Yang, Pei-Jung Lu

المصدر: Cell Death and Disease, Vol 15, Iss 5, Pp 1-15 (2024)

مصطلحات موضوعية: Cytology, QH573-671

الوصف: Abstract Breast cancer (BC) is the most common cancer and the leading cause of cancer-related deaths in women worldwide. The 5-year survival rate is over 90% in BC patients, but once BC cells metastasis into distal organs, it is dramatically decreasing to less than 30%. Especially, triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. Understanding the underline mechanisms of TNBC metastasis is a critical issue. Non-coding RNAs, including of lncRNAs and microRNAs, are non-protein-coding transcripts and have been reported as important regulators in TNBC metastasis. However, the underline mechanisms for non-coding RNAs regulating TNBC metastasis remain largely unclear. Here, we found that lncRNA MIR4500HG003 was highly expressed in highly metastatic MDA-MB-231 TNBC cells and overexpression of MIR4500HG003 enhanced metastasis ability in vitro and in vivo and promoted MMP9 expression. Furthermore, we found MIR4500HG003 physically interacted with miR-483-3p and reporter assay showed miR-483-3p attenuated MMP9 expression. Importantly, endogenous high expressions of MIR4500HG003 were correlated with tumor recurrence in TNBC patients with tumor metastasis. Taken together, our findings suggested that MIR4500HG003 promotes metastasis of TNBC through miR-483-3p-MMP9 signaling axis and may be used as potential prognostic marker for TNBC patients.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-4889Test

الوصول الحر: https://doaj.org/article/0e72ccd055a6489e86d1063eb6f30659Test

المؤلفون: Chien‐Hsiu Li, Chih‐Yeu Fang, Ming‐Hsien Chan, Pei‐Jung Lu, Luo‐Ping Ger, Jan‐Show Chu, Yu‐Chan Chang, Chi‐Long Chen, Michael Hsiao

المصدر: The Journal of Pathology: Clinical Research, Vol 9, Iss 3, Pp 165-181 (2023)

مصطلحات موضوعية: F11R, breast cancer, EP300, survival curve, transcriptomics, Pathology, RB1-214

الوصف: Abstract Cancer progression is influenced by junctional adhesion molecule (JAM) family members. The relationship between JAM family members and different types of cancer was examined using The Cancer Genome Atlas dataset. mRNA levels of the F11R (F11 receptor) in tumours were inversely correlated to the expression of JAM‐2 and JAM‐3. This relationship was unique to breast cancer (BCa) and was associated with poor prognosis (p = 0.024, hazard ratio = 1.44 [1.05–1.99]). A 50‐gene molecular signature (prediction analysis of microarray 50) was used to subtype BCa. F11R mRNA expression significantly increased in human epidermal growth factor receptor 2 (HER2)‐enriched (p = 0.0035) and basal‐like BCa tumours (p = 0.0005). We evaluated F11R protein levels in two different compositions of BCa subtype patient tissue array cohorts to determine the relationship between BCa subtype and prognosis. Immunohistochemistry staining revealed that a high F11R protein level was associated with poor overall survival (p

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2056-4538Test

الوصول الحر: https://doaj.org/article/3a1e9cee83ae4a3ab665b21686e958baTest

المؤلفون: Cheng‐Han Lin, Tai‐I Hsu, Pei‐Yu Chiou, Michael Hsiao, Wen‐Ching Wang, Yu‐Chia Chen, Jen‐Tai Lin, Jaw‐Yuan Wang, Peng‐Chan Lin, Forn‐Chia Lin, Yu‐Kai Tseng, Hui‐Chuan Cheng, Chi‐Long Chen, Pei‐Jung Lu

المصدر: Molecular Oncology, Vol 14, Iss 10, Pp 2574-2588 (2020)

مصطلحات موضوعية: colon cancers, STK4, β‐catenin, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Mammalian STE20‐like kinase 1 (MST1/STK4/KRS2) encodes a serine/threonine kinase that is the mammalian homolog of Drosophila Hippo. STK4 plays an important role in controlling cell growth, apoptosis, and organ size. STK4 has been studied in many cancers with previous studies indicating an involvement in colon cancer lymph node metastasis and highlighting its potential as a diagnostic marker for colon cancer. However, the role of STK4 defect in promoting colon cancer progression is still understudied. Here, we found that STK4 was significantly downregulated in colon cancer and was associated with distal metastasis and poor survival. Furthermore, STK4 knockdown enhanced sphere formation and metastasis in vitro and promoted tumor development in vivo. We found that STK4 colocalized with β‐catenin and directly phosphorylated β‐catenin resulting in its degradation via the ubiquitin‐mediated pathway. This may suggest that STK4 knockdown causes β‐catenin phosphorylation failure and subsequently β‐catenin accumulation, consequently leading to anchorage‐independent growth and metastasis in colon cancer. Our results support that STK4 may act as a potential candidate for the assessment of β‐catenin‐mediated colon cancer prognosis.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1574-7891Test; https://doaj.org/toc/1878-0261Test

الوصول الحر: https://doaj.org/article/c86687411b294698969e3c1dc451cebcTest

المؤلفون: Chiu-Yi Ho, Yu-Te Lin, Hsin-Hung Chen, Wen-Yu Ho, Gwo-Ching Sun, Michael Hsiao, Pei-Jung Lu, Pei-Wen Cheng, Ching-Jiunn Tseng

المصدر: Journal of Neuroinflammation, Vol 17, Iss 1, Pp 1-12 (2020)

مصطلحات موضوعية: Nucleus tractus solitarii, Fractalkine, CX3CR1, Hypertension, Inflammation, Neurology. Diseases of the nervous system, RC346-429

الوصف: Abstract Background Inflammation is a common pathophysiological trait found in both hypertension and cardiac vascular disease. Recent evidence indicates that fractalkine (FKN) and its receptor CX3CR1 have been linked to inflammatory response in the brain of hypertensive animal models. Here, we investigated the role of CX3CR1-microglia in nitric oxide (NO) generation during chronic inflammation and systemic blood pressure recovery in the nucleus tractus solitarii (NTS). Methods The hypertensive rat model was used to study the role of CX3CR1-microglia in NTS inflammation following hypertension induction by oral administration of 10% fructose water. The systolic blood pressure was measured by tail-cuff method of non-invasive blood pressure. The CX3CR1 inhibitor AZD8797 was administered intracerebroventricularly (ICV) in the fructose-induced hypertensive rat. Using immunoblotting, we studied the nitric oxide synthase signaling pathway, NO concentration, and the levels of FKN and CX3CR1, and pro-inflammatory cytokines were analyzed by immunohistochemistry staining. Results The level of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, FKN, and CX3CR1 were elevated two weeks after fructose feeding. AZD8797 inhibited CX3CR1-microglia, which improved the regulation of systemic blood pressure and NO generation in the NTS. We also found that IL-1β, IL-6, and TNF-α levels were recovered by AZD8797 addition. Conclusion We conclude that CX3CR1-microglia represses the nNOS signaling pathway and promotes chronic inflammation in fructose-induced hypertension. Collectively, our results reveal the role of chemokines such as IL-1β, IL-6, and TNF-α in NTS neuroinflammation with the involvement of FKN and CX3CR1.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s12974-020-01857-7Test; https://doaj.org/toc/1742-2094Test

الوصول الحر: https://doaj.org/article/ddefea7ce1bc4134b9612afa424c3dcfTest

المؤلفون: Yu-Cheng Lee, Cheng-Han Lin, Wei-Lun Chang, Wen-Der Lin, Jhih-Kai Pan, Wei-Jan Wang, Bor-Chyuan Su, Hsien-Hui Chung, Chen-Hsun Tsai, Forn-Chia Lin, Wen-Ching Wang, Pei-Jung Lu

المصدر: International Journal of Molecular Sciences, Vol 23, Iss 8, p 4367 (2022)

مصطلحات موضوعية: acquired concurrent chemoradiotherapy resistance, microRNA, epithelial to mesenchymal conversion, esophageal cancer, cell plasticity, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Esophageal squamous cell carcinoma (ESCC) is a common and fatal malignancy with an increasing incidence worldwide. Over the past decade, concurrent chemoradiotherapy (CCRT) with or without surgery is an emerging therapeutic approach for locally advanced ESCC. Unfortunately, many patients exhibit poor response or develop acquired resistance to CCRT. Once resistance occurs, the overall survival rate drops down rapidly and without proper further treatment options, poses a critical clinical challenge for ESCC therapy. Here, we utilized lab-created CCRT-resistant cells as a preclinical study model to investigate the association of chemoradioresistantresistance with miRNA-mediated cell plasticity alteration, and to determine whether reversing EMT status can re-sensitize refractory cancer cells to CCRT response. During the CCRT treatment course, refractory cancer cells adopted the conversion of epithelial to mesenchymal phenotype; additionally, miR-200 family members were found significantly down-regulated in CCRT resistance cells by miRNA microarray screening. Down-regulated miR-200 family in CCRT resistance cells suppressed E-cadherin expression through snail and slug, and accompany with an increase in N-cadherin. Rescuing expressions of miR-200 family members in CCRT resistance cells, particularly in miR-200b and miR-200c, could convert cells to epithelial phenotype by increasing E-cadherin expression and sensitize cells to CCRT treatment. Conversely, the suppression of miR-200b and miR-200c in ESCC cells attenuated E-cadherin, and that converted cells to mesenchymal type by elevating N-cadherin expression, and impaired cell sensitivity to CCRT treatment. Moreover, the results of ESCC specimens staining established the clinical relevance that higher N-cadherin expression levels associate with the poor CCRT response outcome in ESCC patients. Conclusively, miR-200b and miR-200c can modulate the conversion of epithelial–mesenchymal phenotype in ESCC, and thereby altering the response of cells to CCRT treatment. Targeting epithelial–mesenchymal conversion in acquired CCRT resistance may be a potential therapeutic option for ESCC patients.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/23/8/4367Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/5e670e19418e4885843afcf492832948Test

المؤلفون: Cheng-Han Lin, Hao-Yi Li, Yu-Peng Liu, Pei-Fung Kuo, Wen-Ching Wang, Forn-Chia Lin, Wei-Lun Chang, Bor-Shyang Sheu, Yi-Ching Wang, Wan-Chun Hung, Hui-Chuan Cheng, Yun-Chin Yao, Marcus J. Calkins, Michael Hsiao, Pei-Jung Lu

المصدر: Therapeutic Advances in Medical Oncology, Vol 11 (2019)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Background: Esophageal squamous cell carcinoma (ESCC) is the major type of esophageal cancer in Asia and demonstrates poor survival rates following a therapeutic regimen. Methods: Cancer stem cells (CSCs) are responsible for tumor initiation, progression, and treatment failure in cancers. Therefore, identification and characterization of CSCs may help to improve clinical outcomes for ESCC patients. Tumor sphere formation assay are performed to isolate cancer stem-like ESCC cells. QRT-PCR, tumor initiation, metastasis, CCRT treatment are used to evaluate ESCC cells’ stemness properties in vitro and in vivo . Results: The authors’ data demonstrates that cancer stem-like ESCC cells harbored stemness characteristics including self-renewal, differentiation, and transdifferentiation, and possess tumor initiation, metastasis, and treatment inefficiency properties. For the identification of useful biomarkers of cancer stem-like ESCC cells, the authors further identified that CLDN4 was upregulated in cancer stem-like ESCC cells when compared with bulk cancer cells. High-CLDN4 cells harbored stemness and cisplatin/concurrent chemoradiation therapy (CCRT) resistance properties and a high level of CLDN4 was correlated with poor prognosis and poor CCRT response in ESCC patients. Importantly, thiamine tetrahydrofurfuryl disulfide (TTFD) decreased CLDN4 and attenuated stemness in ESCC cells, and TTFD combined with CCRT improved CCRT response in vivo . Conclusions: CLDN4 was suggested as prognostic and a CCRT response indicator for ESCC patients. TTFD combined with CCRT has potential to improve ESCC patient’s clinical outcomes in the future.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1758-8359Test

الوصول الحر: https://doaj.org/article/b18e9d44a0d441e58728c73a619a16f4Test

المؤلفون: Chien-Hsiu Li, Tai-I Hsu, Yu-Chan Chang, Ming-Hsien Chan, Pei-Jung Lu, Michael Hsiao

المصدر: Biomedicines, Vol 9, Iss 9, p 1265 (2021)

مصطلحات موضوعية: EMT, MET, embryonic, tissue repair, tumorigenesis, Biology (General), QH301-705.5

الوصف: Epithelial and mesenchymal transition mechanisms continue to occur during the cell cycle and throughout human development from the embryo stage to death. In embryo development, epithelial-mesenchymal transition (EMT) can be divided into three essential steps. First, endoderm, mesoderm, and neural crest cells form, then the cells are subdivided, and finally, cardiac valve formation occurs. After the embryonic period, the human body will be subjected to ongoing mechanical stress or injury. The formation of a wound requires EMT to recruit fibroblasts to generate granulation tissues, repair the wound and re-create an intact skin barrier. However, once cells transform into a malignant tumor, the tumor cells acquire the characteristic of immortality. Local cell growth with no growth inhibition creates a solid tumor. If the tumor cannot obtain enough nutrition in situ, the tumor cells will undergo EMT and invade the basal membrane of nearby blood vessels. The tumor cells are transported through the bloodstream to secondary sites and then begin to form colonies and undergo reverse EMT, the so-called “mesenchymal-epithelial transition (MET).” This dynamic change involves cell morphology, environmental conditions, and external stimuli. Therefore, in this manuscript, the similarities and differences between EMT and MET will be dissected from embryonic development to the stage of cancer metastasis.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2227-9059/9/9/1265Test; https://doaj.org/toc/2227-9059Test

الوصول الحر: https://doaj.org/article/989b4d5d17604d48b8f07dc41faf2646Test

المؤلفون: Hao-Yi Li, Jui-Lin Liang, Yao-Lung Kuo, Hao-Hsien Lee, Marcus J. Calkins, Hong-Tai Chang, Forn-Chia Lin, Yu-Chia Chen, Tai-I Hsu, Michael Hsiao, Luo-Ping Ger, Pei-Jung Lu

المصدر: Breast Cancer Research, Vol 19, Iss 1, Pp 1-14 (2017)

مصطلحات موضوعية: miR-105, miR-93-3p, Biomarker, Cisplatin, Drug resistance, Triple negative breast cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Moreover, chemotherapy only produces 20–30% pathologic complete response. Because miRNAs are frequently dysregulated in breast cancer and have broad tissue effects, individual or combinations of circulating miRNAs may serve as ideal diagnostic, predictive or prognostic biomarkers, as well as therapeutic targets. Understanding the role and mechanism of dysregulated miRNAs in TNBC may help to develop novel diagnostic and prognostic strategy for TNBC patients. Methods The miRNA array profiles of 1299 breast cancer patients were collected from the Metabric database and subjected to analysis of the altered miRNAs between TNBC and non-TNBC. In Student’s t-test and Kaplan-Meier analysis, four upregulated miRNAs correlated with poor survival in TNBC but not in non-TNBC. Four miRNAs were manipulated in multiple cell lines to investigate their functional role in carcinogenesis. From these results, we studied miR-105 and miR-93-3p in greater detail. The level of miR-105 and miR-93-3p were evaluated in 25 breast cancer tumor tissues. In addition, the diagnostic utility of circulating miR-105 and miR-93-3p were examined in 12 normal and 118 breast cancer plasma samples by ROC curve construction. Results miR-105 and miR-93-3p were upregulated and correlated with poor survival in TNBC patients. Both miR-105 and miR-93-3p were found to activate Wnt/β-catenin signaling by downregulation of SFPR1. By this action, stemness, chemoresistance, and metastasis were promoted. Importantly, the combination of circulating miR-105/93-3p may serve as a powerful biomarker for TNBC, even in early-stage disease. Conclusions miR-105/93-3p activates Wnt/β-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells. Most importantly, combined circulating miR-105/93-3p levels represent a prime candidate for development into a diagnostic biomarker for both early- and late-stage TNBC.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s13058-017-0918-2Test; https://doaj.org/toc/1465-542XTest

الوصول الحر: https://doaj.org/article/1554c9dc505642a5aaf7604114037110Test

المؤلفون: Huey-Jiun Ko, Shean-Jaw Chiou, Yu-Hui Wong, Yin-Hsuan Wang, Yun-Ling Lai, Chia-Hua Chou, Chihuei Wang, Joon-Khim Loh, Ann-Shung Lieu, Jiin-Tsuey Cheng, Yu-Te Lin, Pei-Jung Lu, Ming-Ji Fann, Chi-Ying Huang, Yi-Ren Hong

المصدر: Journal of Clinical Medicine, Vol 8, Iss 10, p 1751 (2019)

مصطلحات موضوعية: pka/gskip/gsk3β/tau axis, sh-sy5y, ips cells, cerebrospinal fluid, alzheimer’s disease, Medicine

الوصف: Based on the protein kinase A (PKA)/GSK3β interaction protein (GSKIP)/glycogen synthase kinase 3β (GSK3β) axis, we hypothesized that these might play a role in Tau phosphorylation. Here, we report that the phosphorylation of Tau Ser409 in SHSY5Y cells was increased by overexpression of GSKIP WT more than by PKA- and GSK3β-binding defective mutants (V41/L45 and L130, respectively). We conducted in vitro assays of various kinase combinations to show that a combination of GSK3β with PKA but not Ca2+/calmodulin-dependent protein kinase II (CaMK II) might provide a conformational shelter to harbor Tau Ser409. Cerebrospinal fluid (CSF) was evaluated to extend the clinical significance of Tau phosphorylation status in Alzheimer’s disease (AD), neurological disorders (NAD), and mild cognitive impairment (MCI). We found higher levels of different PKA−Tau phosphorylation sites (Ser214, Ser262, and Ser409) in AD than in NAD, MCI, and normal groups. Moreover, we used the CRISPR/Cas9 system to produce amyloid precursor protein (APPWT/D678H) isogenic mutants. These results demonstrated an enhanced level of phosphorylation by PKA but not by the control. This study is the first to demonstrate a transient increase in phosphor-Tau caused by PKA, but not GSK3β, in the CSF and induced pluripotent stem cells (iPSCs) of AD, implying that both GSKIP and GSK3β function as anchoring proteins to strengthen the cAMP/PKA/Tau axis signaling during AD pathogenesis.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2077-0383/8/10/1751Test; https://doaj.org/toc/2077-0383Test

الوصول الحر: https://doaj.org/article/e34e5700f3684d8b8b41fea09566fb9eTest

المؤلفون: Cheng-Ju Kuo, Jenn-Wei Chen, Hao-Chieh Chiu, Ching-Hao Teng, Tai-I Hsu, Pei-Jung Lu, Wan-Jr Syu, Sin-Tian Wang, Ting-Chen Chou, Chang-Shi Chen

المصدر: Frontiers in Cellular and Infection Microbiology, Vol 6 (2016)

مصطلحات موضوعية: Caenorhabditis elegans, lipopolysaccharide (LPS), Antimicrobial peptides (AMPs), Enterohemorrhagic Escherichia coli (EHEC), Intestinal innate immunity, RfaD/GmhD/WaaD, Microbiology, QR1-502

الوصف: Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is an important foodborne pathogen causing severe diseases in humans worldwide. Currently, there is no specific treatment available for EHEC infection and the use of conventional antibiotics is contraindicated. Therefore, identification of potential therapeutic targets and development of effective measures to control and treat EHEC infection are needed. Lipopolysaccharides (LPS) are surface glycolipids found on the outer membrane of gram-negative bacteria, including EHEC, and LPS biosynthesis has long been considered as potential anti-bacterial target. Here, we demonstrated that the EHEC rfaD gene that functions in the biosynthesis of the LPS inner core is required for the intestinal colonization and pathogenesis of EHEC in vivo. Disruption of the EHEC rfaD confers attenuated toxicity in Caenorhabditis elegans and less bacterial colonization in the intestine of C. elegans and mouse. Moreover, rfaD is also involved in the control of susceptibility of EHEC to antimicrobial peptides and host intestinal immunity. It is worth noting that rfaD mutation did not interfere with the growth kinetics when compared to the wild-type EHEC cells. Taken together, we demonstrated that mutations of the EHEC rfaD confer hypersusceptibility to host intestinal innate immunity in vivo, and suggested that targeting the RfaD or the core LPS synthesis pathway may provide alternative therapeutic regimens for EHEC infection.

وصف الملف: electronic resource

العلاقة: http://journal.frontiersin.org/Journal/10.3389/fcimb.2016.00082/fullTest; https://doaj.org/toc/2235-2988Test

الوصول الحر: https://doaj.org/article/deebe5064b424bdebe88745fc7d4b1dcTest