Publications by authors named "Qingchang Li"

76 Publications

Diagnosis of NUT Carcinoma Despite False-Negative Next-Generation Sequencing Results: A Case Report and Literature Review.

Onco Targets Ther 2021 27;14:4621-4633. Epub 2021 Aug 27.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, 110001, People's Republic of China.

Nuclear protein in testis (NUT) carcinoma (NC) is a poorly differentiated malignant tumor with a poor prognosis, which is caused by the gene rearrangement. Positive staining of NUT using immunohistochemistry (IHC) or gene rearrangement of revealed by genetic analysis, such as fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS), are important strategies used for accurate diagnosis. In the current study, we present a case of NC in an 18-year-old man who had a chief complaint of nasal congestion, nasal bleeding, and anosmia. Magnetic resonance imaging revealed a mass in the nasal cavity and nasal septum. The initial pathological diagnosis was basaloid squamous cell carcinoma. Based on the tumor location and abrupt keratinization, further genetic tests were performed, and NC was diagnosed using FISH, which was further verified by IHC. However, neither DNA-based NGS nor RNA-based NGS revealed the gene rearrangement. Using this case as a basis, we have reviewed the related literature, compared the common diagnostic methods of NC, and discussed the advantages and limitations of current tools employed for molecular analysis of the gene fusion.
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http://dx.doi.org/10.2147/OTT.S327722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407784PMC
August 2021

Benzo[a]pyrene diol epoxide-induced transformed cells identify the significance of hsa_circ_0051488, a ERCC1-derived circular RNA in pulmonary squamous cell carcinoma.

Mol Carcinog 2021 10 28;60(10):684-701. Epub 2021 Jul 28.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China.

ERCC1 is a gene for repairing DNA damage whose function is related to carcinogenic-induced tumorigenesis and the effectiveness of platinum therapies. Circular RNAs (circRNAs) are products of posttranscriptional regulation with pleiotropic effects on the pathogenesis of lung cancer. We aim to identify that specific circRNAs derived from ERCC1 can regulate key biological processes involved in the development of lung cancer. We performed bioinformatics analysis, in vitro experiments, and analyzed clinical samples, to determine the biological features of a certain ERCC1-derived circRNA termed as hsa_circ_0051488 in benzo[a]pyrene diol epoxide-induced malignant transformed cell and lung cancer cell. The well-established model of transformed cells provided an ideal platform for analyzing the molecular characteristics of this circRNA in the malignant transformation of lung epithelial cell, which supports that hsa_circ_0051488 functions in the onset and growth of lung squamous cell carcinoma (LUSC). Further analysis indicates that the absence of hsa_circ_0051488 promoted the proliferation of cells with the malignant phenotype. Extensive experiments confirm that hsa_circ_0051488 is present in the cytoplasm and functioned as a competing endogenous RNA. In particular, hsa_circ_0051488 binds to mir-6717-5p, thereby modulating the expression of SATB2 gene, a lung cancer suppressor. Furthermore, our in silico experiments indicate that SATB2 can inhibit multiple tumor pathways and its expression positively correlated with the tumor suppressor gene CRMP1. These findings suggest a possible regulatory mechanism of hsa_circ_0051488 in LUSC, and that the newly discovered hsa_circ_0051488/miR-6717-5p/SATB2 axis may be a potential route for therapeutic intervention of LUSC.
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http://dx.doi.org/10.1002/mc.23335DOI Listing
October 2021

Noninvasive papillary urothelial carcinoma with pathological features in between low and high grades: A case report.

Medicine (Baltimore) 2021 Apr;100(17):e25693

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.

Rationale: Urinary bladder urothelial carcinoma is the most common malignant tumor in the urinary system, and noninvasive papillary urothelial carcinoma (NIPUC) comprises most bladder malignancies. NIPUC grading is important for therapeutic and clinical protocol selection. Here, we report a case of NIPUC with pathological features in between low (LG-NIPUC) and high (HG-NIPUC) grades NIPUC.

Patient Concerns: A 72-year-old male, presenting with a 20-year history of hypertension and 5 months of hematuria.

Diagnoses: Computed tomography examination revealed a tumor in the urinary bladder neck. Microscopic investigation revealed that most tumor tissue samples had a branching papillary architecture, with well-developed fibrous-vascular cores. Tumor cells were slightly crowded, with somewhat altered cell polarity and cell adhesion. Immunohistochemistry showed positive Ki67 staining, mostly in the basal layer, while p53 staining was rarely positive. These samples were diagnosed as LG-NIPUC. However, a few tumor tissue samples presented mildly fused papillary architectures without cell polarity or adhesion. Most nuclei stained intensely and were pleomorphic. All epithelial tissue layers were ki67 positive, and the p53 positive rate was higher than that in the LG samples. Therefore, these were classified as HG-NIPUC.

Interventions: The tumor was completely resected during lithotomy postural surgery.

Outcomes: The patient is alive with a good recovery during 3 months after the surgery.

Lessons: We diagnosed this patient as having LG-NIPUC with local HG-NIPUC components. HG- and LG-HIPUC have different outcomes. This case is a new challenge for the pathological grading of NIPUC. An intermediate HIPUC grade might need to be added to the original NIPUC grading system.
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http://dx.doi.org/10.1097/MD.0000000000025693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084004PMC
April 2021

Clinicopathologic features and treatment of thymic lymphoepithelioma-like carcinoma: two case reports and literature review.

Am J Transl Res 2021 15;13(3):1896-1903. Epub 2021 Mar 15.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University No. 155 Nanjing North Street, Heping District, Shenyang 110001, Liaoning, China.

Lymphoepithelioma-like carcinoma (LELC) is rare in the thymus, and easily misdiagnosed. To improve its clinicopathologic knowledge, we describe two cases of thymic LELC, and investigate their microscopic and immunohistochemical features, treatment, and follow-up with a review of previously published cases. Two patients in the First Affiliated Hospital of China Medical University underwent complete surgical resection for thymic LELC. They were treated with chemotherapy or radiotherapy after operation. Histologically, tumor cells exhibited nest patterns or showed stripe-shaped infiltration in fibrous tissue containing lymphocytes. Tumor was diffusely positive for pan-cytokeratin (CK), CK19, cluster of differentiation 5 (CD5), CD117, epithelial membrane antigen (EMA), and p63, and negative for TdT. Recent follow-up showed that the two patients were alive with no signs of recurrence. We report two cases of thymic LELC with a review of previously published cases to summarize knowledge of their clinicopathological characteristics, which is necessary for accurate diagnosis and clinical treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014405PMC
March 2021

SPOCK2 Serves as a Potential Prognostic Marker and Correlates With Immune Infiltration in Lung Adenocarcinoma.

Front Genet 2020 10;11:588499. Epub 2020 Nov 10.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.

Lung adenocarcinoma (LUAD) is one of the major types of lung cancer. Tumor-infiltrating immune cells (TIICs) are positively associated with overall survival (OS) in LUAD. The SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 (SPOCK2) is a complex type of secreted proteoglycan involved in forming a protective barrier against viral infection. The purpose of this study was to investigate the relationship between SPOCK2 and TIICs and the prognostic role of SPOCK2 in LUAD. The GEPIA2, GEO, CPTAC, and HPA databases were analyzed to examine both the mRNA and protein expression of SPOCK2 in LUAD. GEPIA2 and the Kaplan-Meier Plotter (KM Plotter) were used to evaluate the prognostic value of SPOCK2 in LUAD patients. TCGA data were examined for a correlation between SPOCK2 expression and clinical characteristics. Gene enrichment analyses were performed to explore the underlying mechanism of SPOCK2 based on LinkedOmics. RegNetwork was used to predict the regulators of SPOCK2. The correlation between SPOCK2 and TIICs, including immune infiltration level and relative proportion was investigated via TIMER. KM Plotter was also used to evaluate the prognostic role of SPOCK2 expression in LUAD with enriched and decreased TIIC subgroups. We found SPOCK2 was significantly downregulated in LUAD compared with that in non-tumor controls and was correlated with clinical parameters. Moreover, a high SPOCK2 expression level predicted better survival. The SPOCK2-associated regulatory network was constructed. SPOCK2 influenced the TIIC infiltration level and relative proportion in LUAD. Furthermore, a high SPOCK2 expression level was associated with a favorable prognosis in enriched CD4 + T cells and macrophage subgroups in LUAD. In conclusion, a high level of SPOCK2 expression predicted favorable prognosis and was significantly correlated with TIICs in LUAD. Therefore, the expression of SPOCK2 may affect the prognosis of LUAD partly due to TIICs.
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http://dx.doi.org/10.3389/fgene.2020.588499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683796PMC
November 2020

Impact of Organizational Support and Social Capital on University Faculties' Working Performance.

Front Psychol 2020 23;11:571559. Epub 2020 Oct 23.

Marketing Department, School of Business Administration, Jimei University, Xiamen, China.

As the major concerns of higher education institutions (HEIs) are teaching, services, and research, this paper describes a region-wide evaluation of institutional performance in relation to universities in Taiwan. The evaluation was based on the perceptions of university professors regarding institutional slack and reputation, as well as internal and external social capital. The study sought answers to several research questions and adopted a survey approach. After choosing 30 universities of various sizes and from different regions, 926 professors were selected randomly as participants. Using PLS-SEM, this study confirms the influence of institutional slack, reputation, and internal and external social capital on performance. The results show that (a) institutional slack and reputation positively affect institutional performance; (b) internal social capital positively and significantly influences the relationships of institutional slack and reputation with performance; and (c) external social capital has a positive moderating effect on the relationship between institutional slack and performance. Concluding this paper, theoretical and managerial implications and suggestions for future studies are proposed.
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http://dx.doi.org/10.3389/fpsyg.2020.571559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644975PMC
October 2020

Sirtuin 5 regulates the proliferation, invasion and migration of prostate cancer cells through acetyl-CoA acetyltransferase 1.

J Cell Mol Med 2020 12 26;24(23):14039-14049. Epub 2020 Oct 26.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.

Sirtuin 5 (SIRT5) is a NAD -dependent class III protein deacetylase, and its role in prostate cancer has not yet been reported. Therefore, to explore the diagnosis and treatment of prostate cancer, we investigated the effect of SIRT5 on prostate cancer. Sirtuin 5 was assessed by immunohistochemistry in 57 normal and cancerous prostate tissues. We found that the tissue expression levels of SIRT5 in patients with Gleason scores ≥7 were significantly different from those in patients with Gleason scores <7 (P < .05, R > 0). Further, mass spectrometry and pathway screening experiments showed that SIRT5 regulated the activity of the mitogen-activated protein kinase (MAPK) pathway, which in turn modulated the expression of MMP9 and cyclin D1. Being a substrate of SIRT5, acetyl-CoA acetyltransferase 1 (ACAT1) was regulated by SIRT5. SIRT5 also regulated MAPK pathway activity through ACAT1. These results revealed that SIRT5 promoted the activity of the MAPK pathway through ACAT1, increasing the ability of prostate cancer cells to proliferate, migrate and invade. Overall, these results indicate that SIRT5 expression is closely associated with prostate cancer progression. Understanding the underlying mechanism may provide new targets and methods for the diagnosis and treatment of the disease.
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http://dx.doi.org/10.1111/jcmm.16016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753991PMC
December 2020

Expression of IFN-induced 2'-5'-oligoadenylate synthetases correlates with immune infiltration, revealing potential targets and new biomarkers for basal-like breast cancer prognosis.

Int Immunopharmacol 2020 Nov 1;88:106916. Epub 2020 Sep 1.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, China; Department of Pathology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China. Electronic address:

Triple-negative breast cancer has been classified as basal-like immune activated (BLIA), basal-like immune-suppressed (BLIS), and two other subtypes, suggesting potential immune therapeutic targets for basal-like breast cancer (BLBC). 2'-5'-Oligoadenylate synthetases (OASs), identified from differentially expressed genes (DEGs) between BLIA and BLIS breast cancers (GSE76124), are involved in antiviral activity induced by interferons. However, the association between the four OASs and prognosis or tumor-infiltrating immune cells (TIICs) remains unclear. Expression, survival data, and immune correlations for OASs in BLBC were assessed using bioinformatics tools. We found that OASs were highly expressed in BLIA breast cancer. Survival analysis suggested that high transcriptional levels of OASs were associated with better overall survival, relapse-free survival, and distant metastasis-free survival in patients with BLBC. Moreover, the prognostic value of OASs with respect to different clinicopathological factors, and especially according to lymph node metastasis, in patients with BLBC was further assessed. Our findings elucidated the expression, prognostic role, and effect of OASs in TIICs on BLBC, which might promote the development of OAS-targeted immunotherapy for BLBC.
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http://dx.doi.org/10.1016/j.intimp.2020.106916DOI Listing
November 2020

Coexistence of Low-Grade Fetal Adenocarcinoma and Adenocarcinoma in situ of the Lung Harboring Different Genetic Mutations: A Case Report and Review of Literature.

Onco Targets Ther 2020 7;13:6675-6680. Epub 2020 Jul 7.

Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China.

Low-grade fetal lung adenocarcinoma (L-FLAC) is an exceptionally rare pulmonary tumor, presenting with unclear histological and molecular features. In particular, the potential driver genes of L-FLAC remain elusive. To date, only five reports have documented genetic aberrations in L-FLAC. In the current study, we describe an unusual case of L-FLAC coexisting with adenocarcinoma in situ (AIS) of the lung, harboring different genetic mutations. A 39-year-old non-smoker female patient was referred to our hospital with the chief complaint of dyspnea for 20 days. Chest computed tomography (CT) revealed a 2.5×1.5×1.5 cm nodule in the right middle lobe, with no mediastinal lymph node enlargement or distant metastases. Thoracoscopic surgery was performed to remove the nodules. Histopathological analysis of the tissue sections, based on findings from immunohistochemical staining, confirmed a diagnosis of L-FLAC coexisting with AIS of the lung. Next-generation sequencing revealed L-FLAC-based mutations in and , and AIS harboring mutations. Currently, the patient remains recurrence-free 17 months after the initial diagnosis. This report presents the first case demonstrating the coexistence of L-FLAC and AIS in the same pulmonary nodule, harboring different genetic mutations. Based on the literature review, this is the second reported case of L-FLAC bearing mutations.
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http://dx.doi.org/10.2147/OTT.S260993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354012PMC
July 2020

TMED3 Promotes Proliferation and Migration in Breast Cancer Cells by Activating Wnt/β-Catenin Signaling.

Onco Targets Ther 2020 19;13:5819-5830. Epub 2020 Jun 19.

College of Basic Medical Sciences, China Medical University and Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.

Purpose: Evidence describing TMED3 in the context of breast cancer is scarce, and the effect of TMED3 on Wnt/β-catenin signaling in breast cancer has not been reported. The objective of this study was to determine the potential physiological functions and molecular mechanisms of TMED3 in breast cancer.

Materials And Methods: Quantitative real-time PCR and Western blot analysis were used to analyze the expression of TMED3 mRNA and protein in 182 paraffin-embedded primary breast cancer tissues and 60 paired noncancerous tissues and 25 fresh primary breast cancer tissues and surrounding adjacent noncancerous tissues. Associations between TMED3 expression and clinicopathologic factors or overall survival were determined. The effects of overexpression or knockdown of TMED3 on proliferation, migration, invasion, and cell cycle progression in breast cancer cell lines were investigated with the Cell Counting Kit-8, clone formation assay, transwell assay, wound healing assay, and flow cytometry, respectively. Immunofluorescence and Western blot analysis were used to detect the expression of cell cycle, migration-related, and Wnt/β-catenin signaling proteins.

Results: The expression of TMED3 mRNA and protein were significantly increased in breast cancer tissues and cell lines compared to normal controls. TMED3 upregulation was significantly correlated with clinicopathologic characteristics and predicted poor prognosis in patients with breast cancer. TMED3 overexpression promoted proliferation, migration, invasion, and cell cycle progression compared to controls in breast cancer cell lines. TMED3 knockdown suppressed proliferation, migration, invasion, and cell cycle progression compared to controls in breast cancer cell lines. TMED3 promoted proliferation and migration of breast cancer cells by a mechanism that involved Wnt/β-catenin signaling.

Conclusion: TMED3 behaves as an oncogene that promotes the proliferation and migration of breast cancer cells by a mechanism that involved Wnt/β-catenin signaling. Strategies targeting TMED3 have potential therapeutic implications for patients with breast cancer.
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http://dx.doi.org/10.2147/OTT.S250766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311187PMC
June 2020

Apatinib, a Novel Tyrosine Kinase Inhibitor, Promotes ROS-Dependent Apoptosis and Autophagy via the Nrf2/HO-1 Pathway in Ovarian Cancer Cells.

Oxid Med Cell Longev 2020 13;2020:3145182. Epub 2020 May 13.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang 110122, China.

Apatinib, a new-generation oral tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway, shows favorable therapeutic effects in various malignant tumors. However, its effect on ovarian cancer has not yet been characterized. Here, we demonstrated that apatinib inhibited ovarian cancer cell growth and migration in a concentration-dependent manner. Further, we found that apatinib could directly act on tumor cells and promote ROS-dependent apoptosis and autophagy. Mechanistically, we showed that apatinib suppressed glutathione to generate ROS via the downregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway and maintained an antitumor effect at a low level of VEGFR2 in ovarian cancer, suggesting that combination of apatinib with Nrf2 inhibitor may be a promising therapy strategy for patients with ovarian cancer.
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http://dx.doi.org/10.1155/2020/3145182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244982PMC
December 2020

Long noncoding RNA LINC00657 enhances the malignancy of pancreatic ductal adenocarcinoma by acting as a competing endogenous RNA on microRNA-433 to increase PAK4 expression.

Cell Cycle 2020 04 1;19(7):801-816. Epub 2020 Mar 1.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R.China.

A long noncoding RNAs (lncRNA) called is dysregulated and contributes to tumor progression in a number of human cancer types. However, there is limited information on the expression profile and functions of in pancreatic ductal adenocarcinoma (PDAC). The expression profile of in PDAC was estimated by reverse-transcription quantitative polymerase chain reaction (RT-qPCR). The effects of upregulation on PDAC cell proliferation, apoptosis, migration, and invasion in vitro and tumor growth in vivo were explored using CCK-8, flow cytometry, Transwell migration and invasion assays, and a xenograft tumor formation experiment, respectively. The results revealed that was evidently upregulated in the PDAC tumors and cell lines. High expression significantly correlated with the pathological T stage, lymph node metastasis, and shorter overall survival. Functional analysis demonstrated that knockdown inhibited the proliferation, migration, and invasion while promoted the apoptosis of PDAC cells. In addition, knockdown markedly suppressed tumor growth of these cells in vivo. In terms of the mechanism, could directly interact with microRNA-433 (miR-433) and effectively worked as an miR-433 sponge, thus decreasing the competitive binding of miR-433 to mRNA and ultimately increasing PAK4 expression. The actions of knockdown on malignant phenotype of PDAC cells were strongly attenuated by miR-433 inhibition and PAK4 restoration. These results indicate that promotes PDAC progression by increasing the output of the miR-433-PAK4 regulatory loop, thus highlighting the importance of the -miR-433-PAK4 network in PDAC pathogenesis.
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http://dx.doi.org/10.1080/15384101.2020.1731645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145330PMC
April 2020

Carotenoid Cleavage Dioxygenases: Identification, Expression, and Evolutionary Analysis of This Gene Family in Tobacco.

Int J Mol Sci 2019 Nov 18;20(22). Epub 2019 Nov 18.

National Tobacco Cultivation & Physiology & Biochemistry Research Centre, College of Tobacco Science, Henan Agricultural University, Zhengzhou 450002, China.

Carotenoid cleavage dioxygenases (CCDs) selectively catalyze carotenoids, forming smaller apocarotenoids that are essential for the synthesis of apocarotenoid flavor, aroma volatiles, and phytohormone ABA/SLs, as well as responses to abiotic stresses. Here, 19, 11, and 10 genes were identified in , , and respectively. For this family, we systematically analyzed phylogeny, gene structure, conserved motifs, gene duplications, -elements, subcellular and chromosomal localization, miRNA-target sites, expression patterns with different treatments, and molecular evolution. genes were classified into two subfamilies and nine groups. Gene structures, motifs, and tertiary structures showed similarities within the same groups. Subcellular localization analysis predicted that family genes are cytoplasmic and plastid-localized, which was confirmed experimentally. Evolutionary analysis showed that purifying selection dominated the evolution of these genes. Meanwhile, seven positive sites were identified on the ancestor branch of the tobacco CCD subfamily. -regulatory elements of the promoters were mainly involved in light-responsiveness, hormone treatment, and physiological stress. Different family genes were predominantly expressed separately in roots, flowers, seeds, and leaves and exhibited divergent expression patterns with different hormones (ABA, MeJA, IAA, SA) and abiotic (drought, cold, heat) stresses. This study provides a comprehensive overview of the gene family and a foundation for future functional characterization of individual genes.
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http://dx.doi.org/10.3390/ijms20225796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888377PMC
November 2019

Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion.

Blood 2020 01;135(2):108-120

Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.

NF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.
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http://dx.doi.org/10.1182/blood.2019001438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952829PMC
January 2020

SIRT4 enhances the sensitivity of ER-positive breast cancer to tamoxifen by inhibiting the IL-6/STAT3 signal pathway.

Cancer Med 2019 11 1;8(16):7086-7097. Epub 2019 Oct 1.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Recent advances in endocrine therapy have improved the prospects for estrogen receptor-positive breast cancer. Tamoxifen is an effective drug for patients with estrogen receptor-positive breast cancer, but the development of resistance is common. Therefore, discovering ways to enhance the sensitivity of cancer cells to tamoxifen may help improve breast cancer treatment. We studied the biological role of sirtuin 4 (SIRT4) in tamoxifen-treated MCF7 and T47D cells. The levels of the MYC proto-oncogene (MYC) and cyclin D1 (CCND1) were detected by western blotting and quantitative reverse transcription-polymerase chain reaction in breast cancer cells with SIRT4 overexpression or depletion. Immunofluorescence and western blotting were used to assess the phosphorylation status of signal transducer and activator of transcription 3 (STAT3). SIRT4 overexpression decreased the half maximal inhibitory concentration of tamoxifen in MCF7 and T47D cells, while its depletion increased it. Thus, SIRT4 enhances the sensitivity of breast cancer cells to tamoxifen. Moreover, western blotting revealed decreased STAT3 phosphorylation after SIRT4 transfection. The transcription and translation of MYC and CCND1, target genes of the STAT3 pathway, were also blocked. Immunofluorescence revealed that pathway activation and nuclear STAT4 translocation were suppressed when SIRT4 was overexpressed. Furthermore, the effects of SIRT4 overexpression or depletion on proliferation could be offset by STAT3 activation or inhibition. Taken together, these results demonstrate that SIRT4 enhances the tamoxifen sensitivity of breast cancer cells by inhibiting the STAT3 signaling pathway. With this knowledge, therapeutic strategies with reduced drug resistance risk may be developed.
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http://dx.doi.org/10.1002/cam4.2557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853819PMC
November 2019

Comprehensive Analysis of Expression and Prognostic Value of Sirtuins in Ovarian Cancer.

Front Genet 2019 13;10:879. Epub 2019 Sep 13.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.

Sirtuins (SIRTs) 1-7 are a family of intracellular enzymes, which possess nicotinamide adenine dinucleotide-dependent deacetylase activity. Emerging evidence suggest that SIRTs play vital roles in tumorigenesis by regulating energy metabolism, DNA damage repair, genome stability, and other cancer-associated cellular processes. However, the distinct roles of the seven members in ovarian cancer (OC) remain elusive. The transcriptional expression patterns, prognostic values, and genetic alterations of seven SIRTs in OC patients were investigated in this study using a range of databases: Oncomine and Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter, the Cancer Genome Atlas, and cBioPortal. The protein-protein interaction networks of SIRTs were assessed in the String database. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway were analyzed in Database for Annotation, Visualization, and Integrated Discovery. The mRNA expression levels of SIRT1-4 and 7 were downregulated, while that of SIRT5 was upregulated and SIRT6 exhibited both expression dysregulation in patients with OC. Dysregulated SIRTs mRNA expression levels were associated with prognosis. Moreover, genetic alterations primarily occurred in SIRT2, 5, and 7. Network analysis indicated that SIRTs and their 20 interactors were associated with tumor-related pathways. This comprehensive bioinformatics analysis revealed that SIRT1-4, 6, and 7 may be new prognostic biomarkers, while SIRT5 is a potential target for accurate therapy for patients with OC, but further studies are needed to confirm this notion. These findings will contribute to a better understanding of the distinct roles of SIRTs in OC.
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http://dx.doi.org/10.3389/fgene.2019.00879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754078PMC
September 2019

Rsf‑1 regulates malignant melanoma cell viability and chemoresistance via NF‑κB/Bcl‑2 signaling.

Mol Med Rep 2019 Oct 23;20(4):3487-3498. Epub 2019 Aug 23.

Department of Pathology, China Medical University, Shenyang, Liaoning 110001, P.R. China.

Remodeling and spacing factor 1 (Rsf‑1) has been reported as overexpressed in numerous cancers; however, its expression, biological functions and mechanisms in malignant melanoma remain unknown. In the present study, the expression of Rsf‑1 was investigated in 50 cases of malignant melanoma samples using immunohistochemistry. The results revealed that Rsf‑1 expression was elevated in 38% of specimens. MTT, colony formation, Transwell and flow cytometry assays were performed to investigate the functions of Rsf‑1. Knockdown of Rsf‑1 in the MV3 and A375 melanoma cell lines decreased the viability, invasion and cell cycle transition of cells. Conversely, overexpression of Rsf‑1 in M14 cells with low endogenous Rsf‑1 expression induced opposing effects. Further analysis revealed that Rsf‑1 knockdown decreased matrix metalloproteinase‑2, cyclin E and phosphorylated‑IκB expression. Additionally, Rsf‑1 depletion reduced cisplatin resistance and significantly increased the cisplatin‑associated apoptotic rate, whereas Rsf‑1 overexpression exhibited opposing effects. Rsf‑1 also maintained the mitochondrial membrane potential following cisplatin treatment. Analysis of apoptosis‑associated proteins revealed that Rsf‑1 positively regulated B‑cell lymphoma 2 (Bcl‑2), cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2, and downregulated Bcl‑2‑associated X protein expression. Nuclear factor κ‑light‑chain‑enhancer of activated B‑cells (NF‑κB) inhibition reversed the effects of Rsf‑1 on Bcl‑2. In conclusion, Rsf‑1 was overexpressed in malignant melanoma and may contribute to the malignant behaviors of melanoma cells, possibly via the regulation of NF‑κB signaling. Therefore, Rsf‑1 may be a potential therapeutic target in the treatment of malignant melanoma.
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http://dx.doi.org/10.3892/mmr.2019.10610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755232PMC
October 2019

SIRT5 Promotes Cisplatin Resistance in Ovarian Cancer by Suppressing DNA Damage in a ROS-Dependent Manner via Regulation of the Nrf2/HO-1 Pathway.

Front Oncol 2019 13;9:754. Epub 2019 Aug 13.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.

Sirtuin 5 (SIRT5), a mitochondrial class III NAD-dependent deacetylase, plays controversial roles in tumorigenesis and chemoresistance. Accordingly, its role in ovarian cancer development and drug resistance is not fully understood. Here, we demonstrate that SIRT5 is increased in ovarian cancer tissues compared to its expression in normal tissues and this predicts a poor response to chemotherapy. SIRT5 levels were also found to be higher in cisplatin-resistant SKOV-3 and CAOV-3 ovarian cancer cells than in cisplatin-sensitive A2780 cells. Furthermore, this protein was revealed to facilitate ovarian cancer cell growth and cisplatin-resistance . Mechanistically, we show that SIRT5 contributes to cisplatin resistance in ovarian cancer by suppressing cisplatin-induced DNA damage in a reactive oxygen species (ROS)-dependent manner via regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway.
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http://dx.doi.org/10.3389/fonc.2019.00754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700301PMC
August 2019

Trigonelline reduced diabetic nephropathy and insulin resistance in type 2 diabetic rats through peroxisome proliferator-activated receptor-γ.

Exp Ther Med 2019 Aug 21;18(2):1331-1337. Epub 2019 Jun 21.

Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Trigonelline has been reported to serve an important role in cell cycle control, oxidative and ultraviolet stress and DNA methylation. In the present study, the effects of trigonelline were examined on type-2 diabetes mellitus (T2DM)-induced renal dysfunction, and its possible mechanism was investigated. Sprague-Dawley rats were fed with high-fat diet (HFD) for 4 weeks and intraperitoneally injected with 35 mg/kg of streptozotocin for 4 weeks. As a result, trigonelline increased body weight, inhibited the kidney weight/body weight ratio and blood glucose levels, and reduced the levels of blood urea nitrogen, creatinine and albumin in type 2 diabetic rats. In addition, trigonelline also reduced inflammation, oxidative stress and kidney cell apoptosis in T2DM rats. In terms of the molecular mechanisms involved, trigonelline induced the protein expression of peroxisome proliferator-activated receptor (PPAR)-γ and suppressed glucose transporter 4 but suppressed the protein expression of tumor necrosis factor-α and leptin in T2DM rats. The present results demonstrated that trigonelline reduced diabetic nephropathy and insulin resistance in T2DM rats through PPAR-γ.
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http://dx.doi.org/10.3892/etm.2019.7698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614738PMC
August 2019

The MHC class I-LILRB1 signalling axis as a promising target in cancer therapy.

Scand J Immunol 2019 Nov 23;90(5):e12804. Epub 2019 Jul 23.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, China.

Immune checkpoint inhibitors are among the newest, cutting-edge methods for the treatment of cancer. Currently, they primarily influence T cell adaptive immunotherapy targeting the PD-1/PD-L1 and CTLA-4/B7 signalling pathways. These inhibitors fight cancer by reactivating the patient's own adaptive immune system, with good results in many cancers. With the discovery of the "Don't Eat Me" molecule, CD47, antibody-based drugs that target the macrophage-related innate immunosuppressive signalling pathway, CD47-SIRPα, have been developed and have achieved stunning results in the laboratory and the clinic, but there remain unexplained instances of tumour immune escape. While investigating the immunological tolerance of cancer to anti-CD47 antibodies, a second "Don't Eat Me" molecule on tumour cells, beta 2 microglobulin (β2m), a component of MHC class I, was described. Some tumour cells reduce their surface expression of MHC class I to escape T cell recognition. However, other tumour cells highly express β2m complexed with the MHC class I heavy chain to send a "Don't Eat Me" signal by binding to leucocyte immunoglobulin-like receptor family B, member 1 (LILRB1) on macrophages, leading to a loss of immune surveillance. Investigating the mechanisms underlying this immunosuppressive MHC class I-LILRB1 signalling axis in tumour-associated macrophages will be useful in developing therapies to restore macrophage function and control MHC class I signalling in patient tumours. The goal is to promote adaptive immunity while suppressing the innate immune response to tumours. This work will identify new therapeutic targets for the development of pharmaceutical-based tumour immunotherapy.
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http://dx.doi.org/10.1111/sji.12804DOI Listing
November 2019

Fbxo6 confers drug-sensitization to cisplatin via inhibiting the activation of Chk1 in non-small cell lung cancer.

FEBS Lett 2019 07 7;593(14):1827-1836. Epub 2019 Jun 7.

Department of Pathology, The First Affiliated Hospital and the Basic Medical Sciences of China Medical University, Shenyang, China.

Fbxo6 (also called FBG2) is a critical component of the evolutionarily conserved ubiquitin-protein ligase complex SCF (Skp1/Cdc53-Cullin1/F-box). Previous studies have demonstrated that Fbxo6 facilitates the growth and proliferation but inhibits the apoptosis and invasion of gastric cancer cells. However, the role of Fbxo6 in non-small cell lung cancer (NSCLC) is still not clear. Our results revealed that Fbxo6 expression is correlated with early TNM stage and favorable overall survival of NSCLC patients. Further in vitro experiments showed that Fbxo6 inhibits proliferation, facilitates apoptosis and promotes the sensitivity of cisplatin via decreased expression and phosphorylation of Chk1. Thus, Fbxo6 may be a useful prognosis marker and therapeutic target to overcome the chemoresistance of cisplatin-based chemotherapy agents in NSCLC patients.
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http://dx.doi.org/10.1002/1873-3468.13461DOI Listing
July 2019

CCDC85B promotes non-small cell lung cancer cell proliferation and invasion.

Mol Carcinog 2019 01 9;58(1):126-134. Epub 2018 Oct 9.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Coiled-coil domain containing 85 B (CCDC85B) is involved in diverse biological processes; however, its expression patterns and functions in human cancers are yet unknown. The present study demonstrated that the expression of CCDC85B in the cytoplasm of the non-small cell lung cancer (NSCLC) tumor cells was significantly higher compared to adjacent normal lung tissues (P < 0.05). Furthermore, CCDC85B expression correlated with advanced TNM stage (P = 0.004) and positive regional lymph node metastasis (P = 0.009) of NSCLC. In addition, in A549 and H1299 lung cancer cell lines, the overexpression of CCDC85B promoted cell proliferation and invasion, while siRNA-mediated CCDC85B knockdown exhibited opposite effects. CCDC85B promoted AKT and GSK3β phosphorylation and upregulated the levels of active β-catenin, Wnt targets c-myc, cyclin D1, and MMP7. Besides, the CCDC85B-induced upregulation of phosphorylated GSK3β and active β-catenin was rescued following the treatment with PI3 K inhibitor, LY294002. In conclusion, CCDC85B was associated with NSCLC progression as it promoted the proliferation and invasion of lung cancer cells through activated AKT/GSK3β/β-catenin oncogenic signaling pathway. Therefore, CCDC85B might serve as a novel target for NSCLC treatment.
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http://dx.doi.org/10.1002/mc.22914DOI Listing
January 2019

Effects of RSF-1 on proliferation and apoptosis of breast cancer cells.

Oncol Lett 2018 Oct 18;16(4):4279-4284. Epub 2018 Jul 18.

Staff Room of Pathology, China Medical University, College of Basic Medical Science, Shenyang, Liaoning 110001, P.R. China.

Effect of interference with chromatin remodeling and spacing factor-1 (RSF-1) on proliferation and apoptosis of breast cancer cells was investigated. MCF-7 and SKBR-3 cells were cultured and were divided into 3 groups: control group, negative siRNA control group (NC) and RSF-1 siRNA group. Western blot analysis was used to detect the expression of RSF protein after interference. Cell Counting Kit-8 (CCK-8) method was used to detect the effect of RSF-1 siRNA on cell proliferation. Plate cloning assay was used to detect the effect of RSF-1 siRNA on cell clone formation ability. Annexin V/PI double staining method was used to detect the effect of RSF-1 siRNA on cell apoptosis. Effect of RSF-1 siRNA on nuclear factor-κB (NF-κB) and its downstream signaling pathway were detected by western blot analysis. Western blot analysis showed that RSF-1 siRNA significantly downregulated the expression of RSF-1 protein in MCF-7 and SKBR-3 cells at 72 h after transfection (P<0.01). Cell proliferation assay showed that RSF-1 siRNA significantly reduced the proliferation ability and clone formation ability of MCF-7 and SKBR-3 cells compared with the control group (P<0.01). Annexin V/PI double staining assay results showed that compared with the control group, RSF-1 siRNA significantly increased the apoptosis rate of MCF-7 and SKBR-3 cells (P<0.01). Helenalin and Rsf-1 siRNA significantly reduced the expression levels of p-p65, Bcl-2, and XIAP proteins (P<0.01). Interfering with the expression of RSF-1, gene can effectively inhibit the proliferation of MCF-7 and SKBR-3 cells and promote their apoptosis. RSF-1 can be used as a potential new therapeutic target for the treatment of breast cancer.
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http://dx.doi.org/10.3892/ol.2018.9172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126160PMC
October 2018

Comparative transcriptome analysis of Paphia undulata with different foot colors.

Mar Genomics 2018 Dec 5;42:25-31. Epub 2018 Sep 5.

Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture, Fisheries College, Jimei University, Xiamen 361021, Fujian, PR China. Electronic address:

Foot color is an important trait in Paphia undulata that influences consumer selection. To elucidate the molecular basis of foot color, six transcriptome libraries of P. undulata with different foot colors were constructed: white (L2, L3 and L4) and orange (D2, D3, D4). There is a significant difference in color index (L, a, b) between the two groups (P < 0.05). These six paired-end libraries were sequenced using the Illumina HiSeq 2500 platform. In total, 48.22 Gb of clean data were obtained and de novo assembled into 58,159 unigenes with a mean length of 889.51 bp and N50 of 1461 bp. A total of 19,070 unigenes were significantly matched to known unique proteins. The Gene Ontology (GO) annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to determine metabolic pathways and candidate genes associated with foot color traits. Compared with white P. undulate, a total of 107 transcripts were identified as differentially expressed genes (DEGs) in orange samples using Cuffdiff, including 74 up-regulated and 33 down-regulated genes. Of these differentially expressed genes, many were involved in the synthesis and transport of carotenoids and pigment biosynthesis. Additionally, results of the transcriptome analysis were verified by quantitative real-time PCR (qRT-PCR). Overall, this experiment discovered several potential foot coloration genes and related molecular mechanisms using RNA-seq, which paves the way for further functional elucidation of color-related genes and assists selective breeding practices in P. undulata.
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http://dx.doi.org/10.1016/j.margen.2018.08.007DOI Listing
December 2018

Remodeling and spacing factor 1 overexpression is associated with poor prognosis in renal cell carcinoma.

Oncol Lett 2018 Mar 15;15(3):3852-3857. Epub 2018 Jan 15.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, Liaoning 110001, P.R. China.

The present study aimed to assess the expression and prognostic significance of remodeling and spacing factor 1 (RSF1; HBXAP) in renal cell carcinoma (RCC). RSF1 expression was analyzed using immunohistochemistry on tissue samples from a consecutive series of 137 patients with RCC who underwent tumor resection between November 2000 and March 2004. The associations between RSF1 expression, clinicopathological factors and patient survival were investigated. Immunohistochemistry revealed that RSF1 was highly expressed in 43.1% (59/137) of the RCC samples. RSF1 expression levels were associated with the T stage of the Tumor-Node-Metastasis grading system. Kaplan-Meier survival analysis indicated that high RSF1 expression in RCC was significantly associated with a poor prognosis. Multivariate analysis revealed that RSF1 expression is an independent prognostic parameter for the duration of overall survival of patients with RCC. The results demonstrated that a high expression level of RSF1 in RCC is associated with advanced tumor stages and a poor prognosis. To the best of our knowledge, the present study provides novel evidence of the biological significance of RSF1 expression in RCC.
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http://dx.doi.org/10.3892/ol.2018.7797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796381PMC
March 2018

ARHGEF39 promotes tumor progression via activation of Rac1/P38 MAPK/ATF2 signaling and predicts poor prognosis in non-small cell lung cancer patients.

Lab Invest 2018 05 30;98(5):670-681. Epub 2018 Jan 30.

Department of Pathology, The College of Basic Medicine Science and The First Affiliated Hospital of China Medical University, Shenyang, China.

Rho guanine nucleotide exchange factor 39 (ARHGEF39), also called C9orf100, is a new member of the Dbl-family of guanine nucleotide exchange factors. Although ARHGEF39 has been proven to regulate tumor progression in hepatocellular carcinoma, the downstream signaling pathway of ARHGEF39 and its clinical associations in non-small cell lung cancer (NSCLC) are currently unknown. In the present study, using MTT, colony formation, flow cytometry, mice xenografts, wound healing, and transwell assays, we showed that ARHGEF39 promoted tumor proliferation, migration, and invasion. Furthermore, ARHGEF39 promoted the expression of Cyclin A2, Cyclin D1, and MMP2 by activating Rac1, leading to increased phosphorylation of P38 and ATF2. Treatment with a P38 inhibitor counteracted the effect of ARHGEF39 overexpression on the increase in Cyclin A2, Cyclin D1, and MMP2 expression. Moreover, the elevated levels of p-P38 and p-ATF2 caused by ARHGEF39 overexpression could be inhibited by expression of a dominant negative Rac1 mutant (T17N). In addition, the inhibition of the expression of p-P38 and p-ATF2 by ARHGEF39 RNAi could be restored by the expression of a constitutively active Rac1 mutant (Q61L). A similar impact on cell growth and invasion was observed after ARHGEF39 overexpression combined with the P38 inhibitor, Rac1 T17N, or Rac1 Q61L. Using immunohistochemistry, ARHGEF39 expression was observed to correlate positively with larger tumor size in clinical samples from 109 cases of NSCLC (P = 0.008). The Kaplan-Meier test revealed that ARHGEF39 expression significantly affected the overall survival of patients with NSCLC (52.55 ± 6.40 months vs. 64.30 ± 5.40 months, P = 0.017). In conclusion, we identified that ARHGEF39 promotes tumor growth and invasion by activating the Rac1-P38-ATF2 signaling pathway, as well as increasing the expression of Cyclin A2, Cyclin D1, and MMP2 in NSCLC cells. ARHGEF39 may be a useful marker to predict poor prognosis of patients with NSCLC.
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http://dx.doi.org/10.1038/s41374-018-0022-yDOI Listing
May 2018

Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia.

Cell Rep 2018 01;22(2):350-358

Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address:

Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabilization of NIK-induced activation of NF-κB non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively. Importantly, by querying the connectivity MAP using up- and downregulated genes that are present exclusively in NIK-stabilized LSCs, we discovered that verteporfin has anti-AML effects, suggesting that repurposing verteporfin to target myeloid leukemia is worth testing clinically. Our data provide a scientific rationale for developing small molecules to stabilize NIK specifically in myeloid leukemias as an attractive therapeutic option.
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http://dx.doi.org/10.1016/j.celrep.2017.12.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810947PMC
January 2018

Update on research and application of problem-based learning in medical science education.

Biochem Mol Biol Educ 2018 03 29;46(2):186-194. Epub 2017 Dec 29.

Department of Pathology, College of Basic Medical Sciences of China Medical University, Shenyang 110122, China.

Problem-based learning (PBL) is a unique form of pedagogy dedicated to developing students' self-learning and clinical practice skills. After several decades of development, although applications vary, PBL has been recognized all over the world and implemented by many medical schools. This review summarizes and updates the application and study of PBL in medical education through the literature published between 1993 and early 2017. It focuses on understanding real medical PBL courses and ways to improve PBL to achieve better learning outcomes. PBL aims to develop lifelong skills to solve practical problems rather than limiting learning to theoretical knowledge. To achieve this goal, strict and reasonable procedures need to be designed and implemented. Rigorous monitoring and timely feedback and evaluation are indispensable to constant improvements and perfecting of the process. © 2017 by The International Union of Biochemistry and Molecular Biology, 46(2):186-194, 2018.
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http://dx.doi.org/10.1002/bmb.21105DOI Listing
March 2018

Rsf-1 Influences the Sensitivity of Non-Small Cell Lung Cancer to Paclitaxel by Regulating NF-κB Pathway and Its Downstream Proteins.

Cell Physiol Biochem 2017 15;44(6):2322-2336. Epub 2017 Dec 15.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.

Background/aims: The therapeutic efficacy of paclitaxel is hampered by chemotherapeutic resistance in non-small cell lung cancer (NSCLC). Rsf-1 enhanced paclitaxel resistance via nuclear factor-κB (NF-κB) in ovarian cancer cells and nasopharyngeal carcinoma. This study assessed the function of Rsf-1 in the modulation of the sensitivity of NSCLC to paclitaxel via the NF-κB pathway.

Methods: The mRNA and protein levels of the related genes were quantified by RT-PCR and Western blotting. Rsf-1 silencing was achieved with CRISPR/Cas9 gene editing. Cell cycle, migration and proliferation were tested with flow cytometry, transwell test and CCK8 test. Cell apoptosis was analyzed with flow cytometry and quantification of C-capase3. The parameters of the tumors were measured in H460 cell xenograft mice.

Results: Rsf-1 was highly expressed in H460 and H1299 cells. Rsf-1 knockout caused cell arrest at the G1 phase, increased cell apoptosis, and decreased migration and cell proliferation. Rsf-1 knockout increased the inhibition of cell proliferation, the reduction in cell migration and the augment in cell apoptosis in paclitaxel treated H460 and H1299 cells. Rsf-1 knockout further enhanced the paclitaxel-mediated decrease in the volume and weight of the tumors in H460 cell xenograft mice. Helenalin and Rsf-1 knockout decreased the protein levels of p-P65, BcL2, CFLAR, and XIAP; hSNF2H knockout decreased the protein level of NF-κB p-P65 without altering Rsf-1 and p65 protein levels, while Rsf-1 and hSNF2H double knockout decreased the level of NF-κB p-P65, in H1299 and H460 cells.

Conclusion: These results demonstrate that Rsf-1 influences the sensitivity of NSCLC to paclitaxel via regulation of the NF-κB pathway and its downstream genes.
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http://dx.doi.org/10.1159/000486116DOI Listing
March 2018
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