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Knockdown of eukaryotic translation initiation factor 3 subunit B inhibits cell proliferation and migration and promotes apoptosis by downregulating WNT signaling pathway in acute myeloid leukemia

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

The study aimed to investigate the effect of eukaryotic translation initiation factor 3 subunit B (EIF3B) on cell proliferation, migration, and apoptosis as well as the underlying mechanism in acute myeloid leukemia (AML). EIF3B expression was detected in AML-193, HL-60, OCI-AML2, and KG-1 cell lines and human primary bone marrow mononuclear cells (BMMC). EIF3B knockdown was realized by transfecting EIF3B ShRNA plasmids, and EIF3B knockdown and WNT2 overexpression were established by transfecting EIF3B ShRNA plasmids and WNT2 overexpression plasmids into KG-1 cells. The effect of EIF3B knockdown, and EIF3B knockdown plus WNT2 overexpression on cell proliferation, apoptosis, migration, glycogen synthase kinase 3B (GSK3B) and catenin beta 1 (CTNNB1) was assessed. EIF3B mRNA and protein expression were higher in AML-193, OCL-AML2 and KG-1 cell lines, but unchanged in the HL-60 cell line compared with human primary BMMC. The expression of WNT2 was decreased by EIF3B downregulation, while it had no effect on EIF3B expression. As for cell activities, EIF3B knockdown inhibited the cell proliferation and migration but promoted apoptosis by inhibiting WNT2 expression. In addition, EIF3B knockdown downregulated the expression of CTNNB1 but upregulated the expression of GSK3B by blocking WNT2 expression in AML, implying an inhibitory effect of EIF3B downregulation on WNT signaling pathway. EIF3B is upregulated and its knockdown inhibits cell proliferation, and migration, while promoting apoptosis by downregulating the WNT signaling pathway in AML.

MicroRNA-21 and microRNA-155 promote the progression of Burkitt's lymphoma by the PI3K/AKT signaling pathway

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

Introduction: Burkitt's lymphoma (BL) is a rare and highly aggressive B cell non-Hodgkin lymphoma. High toxicity of chemotherapy for BL treatment causes morbidity and mortality. Many miRNAs have been used as biomarkers for early detection or therapy targets for tumors. However, the roles of miR-21 and miR-155 in Burkitt's lymphoma remain unclear. Methods: We collected 15 blood samples from patients with Burkitt's lymphoma and evaluated the expression of miR-21 and miR-155. Then, we knocked down miR-21 and miR-155 expression in Burkitt's lymphoma cell lines and assessed cell proliferation, cell cycle, and apoptosis. Furthermore, we detected the activation of PI3K/AKT pathway by qPCR and western blot. Finally, we predicted the target genes of miR 21 and miR-155 by publicly available databases. Results: The expression of miR-21 and miR-155 in blood samples from patients with Burkitt's lymphoma were significantly upregulated. Knockdown of miR-21 and miR-155 significantly suppressed cell proliferation, and resulted in S phase arrest and cell apoptosis. The knockdown of miR-21 and miR-155 inhibited the activation of the PI3K/AKT pathway. We found that the target genes of miR-21 and miR-155 were C1RL and TCAP. Conclusion: miR-21 and miR-155 promote the progression of Burkitt's lymphoma through PI3K/AKT signaling by targeting C1RL and TCAP. Our findings will provide a novel biomarker and therapeutic strategies for Burkitt's lymphoma.

Effect of antenatal tetramethylpyrazine on lung development and YAP expression in rat model of experimental congenital diaphragmatic hernia

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

The aim of this study was to investigate the therapeutic effects and underlying mechanism of tetramethylpyrazine (TMP) on lung development using a rat model of congenital diaphragmatic hernia (CDH). Nitrofen was used to induce CDH. Pregnant rats were divided into three groups: control, CDH, and CDH+TMP. In the CDH and CDH+TMP, fetuses only with left diaphragmatic hernias were chosen for analysis. Lung and body weight were recorded and lung histologic evaluations, image analysis, and western blot analysis of YAP, p-YAP and LATS1 were performed after lung processing. A markedly abnormal structure was observed, as evidenced by pulmonary hypoplasia and vascular remodeling, in the CHD. These abnormalities were improved in the CDH+TMP. There were significant differences between the CHD and CHD+TMP in percentage of medial wall thickness, arteriole muscularization, radial alveolar counts, AA%, and alveolar septal thickness. YAP expression was markedly increased in the CHD compared to the controls, which was not affected by antenatal TMP administration. However, prenatal TMP intervention significantly increased expression of LATS1 and phosphorylation of YAP in the CDH fetuses. Our results demonstrate that antenatal TMP administration improved vascular remodeling and promoted lung development in a rat model of CHD, potentially through increasing expression of LATS1 and phosphorylation of YAP.

Discordant lymphoma consisting of mantle cell lymphoma and angioimmunoblastic T cell lymphoma: homology or heterogeneity?

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

Objects: To investigate the pathologic characteristic of discordant lymphoma with mantle cell lymphoma and angioimmunoblastic T cell lymphoma. Methods: The clinicopathologic data of cases of discordant lymphoma were organized and clinicopathologic features were analyzed by literature review. Results: A 49-year-old male was taken to the hospital due to the lymphandenopathy in January 2007 and mantle cell lymphoma was diagnosed in the pathology report. EBV-EBER staining was negative. Active chemotherapy was received and the patient achieved complete response. Seven years later since diagnosis, in 2014 scattered rashes were found. A skin biopsy was taken and the result was not mantle cell lymphoma but angioimmunoblastic T cell lymphoma. EBV-EBER positivity was detected. Clonal T cell receptor gamma locus gene rearrangements were detected while no clonal immunoglobin heavy locus gene rearrangement was detected in the skin sample. Conclusions: This is the first report on discordant lymphoma consisting of mantle cell lymphoma and angioimmunoblastic T cell lymphoma. There seems to be no relation these two different kinds of lymphoma, and EBV infection might prompt the development of angioimmunoblastic T cell lymphoma after transplantation. Rash is a common clinical manifestation when T cell lymphoma develops after treatment for MCL.

Co-expression of HIF-1 and TLR3 is associated with poor prognosis in oral squamous cell carcinoma

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

This study investigates the prognostic impact of the expression of hypoxia inducible factor (HIF)-1 alpha and Toll-like receptor (TLR) 3 detected by immunohistochemistry in oral squamous cell carcinoma (OSCC). The study also evaluates the treatment outcome by inhibition of the HIF-1 alpha and TLR 3 pathway (nuclear factor [NF]-kappa B) in an OSCC transplantation model in nude mice. Statistical analysis of immunohistochemical results with clinical findings that included overall survival outcomes was performed for 90 OSCC patients. Forty nude mice were divided into four groups (control; inhibition of HIF-1 alpha; inhibition of NF-kappa B; and inhibition of HIF-1 alpha and NF-kappa B). Tumor weight and immunohistochemical results of each group were compared. The results show that co-detection of low HIF-1 alpha/TLR3 expression is significantly correlated with a better prognosis for OSCC patients. Use of an inhibitor of the HIF-1 and TLR3 pathway in an OSCC transplantation model shows a good treatment outcome.

Mouse tail models of secondary lymphedema: fibrosis gradually worsens and is irreversible

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

Although the mouse tail model of secondary lymphedema has been widely used in research, our knowledge regarding some of the characteristic changes in this model is lacking. Therefore, in the current study, we aimed to identify pathologic changes after surgery. Tail lymphedema was created in C57BL/6J mice by disconnecting both superficial and deep lymphatic vessels. The surgery resulted in chronic edema formation with the proliferation of subcutaneous adipose tissue, deposition of fibrotic tissue, and gradual increase in CD4(+) T lymphocyte infiltration. Furthermore, dramatic expansion and an increased number of lymphatic vessels were observed postoperatively. Lymphatic reflux was established at least 8 weeks after surgery, as evidenced by staining of the scar from the surgical excision. In addition, tissue fibrosis was irreversible, although CD4(+) T cell infiltration, tail swelling, and subcutaneous adipose hyperplasia were alleviated over time. We also show that necrosis could be effectively avoided by paying attention to several details in the modeling process. As animal models play a key role in exploring the pathophysiology of disease, our findings provide strong support for the study of lymphedema. The irreversibility of fibrosis suggests the importance of treating lymphedema by preventing fibrosis development.

Rapid intraoperative immunocytochemistry of central nervous system tumors

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

Intraoperative pathologic diagnosis for central nervous system (CNS) tumors is important to determine the neurosurgery procedure. But sometimes the differential diagnosis between glioma and lymphoma, or glioma and metastatic tumors is difficult for a pathologist during a short time, especially when the specimen is small or the frozen section has ice crystals. Immunohistochemistry (IHC) is a very useful method for diagnosis, but the traditional immunohistochemical method is time consuming and not suitable intraoperatively. In this study, we chose Cytokeratin-pan, GFAP, and LCA as three immunohistochemical indicators. Intraoperative IHC was done by Novodiax ihcDirect technology combined with Leica Bond auto-staining. Compared with the manual method recommended for the reagents (Novodiax ihcDirect), the results show that auto-staining has better stability and high reproducibility in coloration, which has broad prospects for future application.

Superficial CD34-positive fibroblastic tumor: report of two cases and review of literature

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

Background: We studied the clinicopathologic features of superficial CD34-positive fibroblastic tumor (SCPFT), which is a newly described neoplasm, to enhance the recognition and diagnostic level of the disease. Case presentation: We herein report two cases of superficial CD34-positive fibroblastic tumors in a 33-year-old man and a 30-year-old man. The 33-year-old man presented with a slow-growing subcutaneous nodule 5.0 cm in diameter on the right thigh, and the 30-year-old man developed a painful lump 4.0 cm in diameter on his right thigh. Histologically, the tumor was located in superficial soft tissue with relative circumscription. Tumors had abundant spindled polygonal cells, which were arranged in fascicular or sheet-like patterns. Neoplastic cells were characterized by polymorphic nuclei, granular cytoplasm, intranuclear cytoplasmic pseudoinclusions, and an extremely low mitotic rate. Immunohistochemically, neoplastic cells showed diffuse and strong CD34 expression and focal cytokeratin staining. The expression of S-100 protein, SMA, CD99, H-caldesmon, ALK-1, and bcl-2 were all negative. The Ki-67 index was low. Conclusions: SCPFT is a rare low-grade fibroblastic tumor that has typical morphologic features and unique biologic behavior. Familiarity with clinicopathologic characteristics of the tumor contributes to the differential diagnosis of similar tumors.

Potential value of V-domain Ig suppressor of T-cell activation for assessing progn osis in cervical cancer and as a target for therapy

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

V-domain Ig suppressor of T-cell activation (VISTA), which belongs to the B7 family and is expressed predominantly on hematopoetic cells, myeloid, granulocytic and T cells, can suppresses T cell activation in vivo and vitro. The blockade of VISTA has displayed brilliant results in certain murine tumor models. But to date, little is known about the expression and impact of VISTA in human cervical cancer (CC). To fill this gap of information, we systemically investigated the expression of VISTA on tumor cells, intratumoral immune cells (ICs) and vascular endothelial cells (VECs) in a group of patients with CC by performing immunohistochemical analysis. The associations between VISTA expression and different clinicopathologic features were evaluated using Fisher's exact test, and the analysis of overall survival in different groups was performed by the construction of Kaplan-Meier models. The results indicated that high expression of VISTA on ICs or VECs was significantly related to advanced tumor stage and the lymph node metastasis (LNM) of CC. Furthermore, we performed multivariate Cox regression analysis, which showed that there was no association between VISTA expression and the 5-year overall survival rate, and LNM was the only independent predicting factor of poor prognosis for CC.

Lymphadenopathy in POEMS syndrome: a correlation between clinical features and imaging findings

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

Lymphadenopathy is an important characteristic of POEMS syndrome, and a Castleman disease (CD)-like pathologic change in the lymph nodes is one of the major diagnostic criteria. However, the characteristics of lymphadenopathy in POEMS still have not been completely elucidated. The lymph node biopsies are available only for a small proportion of patients. A simple and safe way is needed to rule CD in or out. This study aimed to analyse the features of lymphadenopathy and estimate the role of imaging methods, including computed tomography (CT) and positron emission tomography-CT (PET/CT), in the diagnosis of lymphadenopathy in patients with POEMS syndrome. We conducted a retrospective analysis of 23 patients with confirmed POEMS syndrome. All of the patients received chest and abdominal CT scan and/or superficial ultrasound examinations. Four patients underwent PET/CT examinations, and 6 patients received lymph node biopsies. Enlarged lymph nodes (short diameter >= 1 cm) were found in 48% (11/23) of patients, but only 1 patient had an enlarged lymph node with a diameter >= 2 cm. Lymph nodes with CD-like pathologic changes from 2 patients showed increased maximum standard uptake values (SUVmax) of F-18-deoxyglucose ((18)FDG) on PET/CT, while lymph nodes with reactive pathologic changes from 2 other patients showed a normal metabolic PET/CT profile. The extent of lymph node enlargement in patients with POEMS was less than that in patients with CD per se. We draw the conclusion that most of the enlarged lymph nodes had diameters <= 2 cm, which is less than that in cases of CD per se and PET/CT may be helpful in determining whether enlarged lymph nodes are characterized by CD-like changes or not.

Clinical significance of RAD51C and its contribution to ovarian carcinogenesis

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

Aim: The underlying mechanisms of chemoresistance-induced recurrence of ovarian carcinoma are largely unknown. The purpose of this study was to investigate the clinical significance of RAD51C and its role in ovarian tumorigenesis and progression. Methods: 60 cases of ovarian epithelial tumors (30 benign and 30 malignant tumors, respectively) were enrolled from 2014 to 2016. Immunohistochemistry was used to evaluate RAD51C expression in tumor tissues, and RT-PCR was employed to test RAD51C mRNA levels in SKOV3, A2780, and CAOV3 cell lines. Targeted knockdown of RAD51C was achieved with siRNA to explore the changes of cell proliferation, migration, and apoptosis. Results: RAD51C protein level in carcinoma tissues, especially in the high-grade group (P<0.001), was significantly higher than that of benign tumors and associated with pathological type, stage, and overall survival (P<0.05). Downregulation of RAD51C promoted apoptosis and decreased cell survival rate and migration. Conclusions: Our results supported that RAD51C contributes to the progression of ovarian carcinoma, suggesting its promising application as an independent prognostic marker for diagnosis and treatment.

Long noncoding RNA NORAD regulates lung cancer cell proliferation, apoptosis, migration, and invasion by the miR-30a-5p/ADAM19 axis

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (1)

Background: Lung cancer is one of the most common human cancers. Long noncoding RNA-activated by DNA damage (NORAD) is often upregulated and promotes cell progression in various human cancers; however, its function and possible mechanism in lung cancer remain largely unknown. Methods: The expression levels of NORAD, miR-30a-5p and a disintegrin and metalloproteinase 19 (ADAM19) were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). 3-(4, 5)-dimethylthiazole-2-y1)-2, 5-biphenyl tetrazolium bromide (MTT) assay, flow cytometry, and transwell assay were employed to detect cell proliferation, apoptosis, migration, and invasion abilities, respectively. Western blot was used to detect the protein expression of ADAM19. The interaction between miR-30a-5p and NORAD or ADAM19 was predicted by online software and confirmed by the dual-luciferase reporter assay. Results: The expression levels of NORAD and ADAM19 were increased and the expression level of miR-30a5p was decreased in lung cancer tissues and cells. Knockdown of NORAD could inhibit cell proliferation, migration and invasion but promote apoptosis in lung cancer cells. In addition, NORAD directly interacted with miR-30a-5p and its overexpression reversed the anti-cancer role of miR-30a-5p in lung cancer. Moreover, miR-30a-5p directly targeted ADAM19 and its inhibition attenuated the inhibitory effect of ADAM19 knockdown on progression of lung cancer cells. Furthermore, NORAD functioned as a competing endogenous RNA (ceRNA) through sponging miR-30a5p to regulate ADAM19 expression. Conclusion: NORAD knockdown suppressed cell proliferation, migration and invasion but promoted cell apoptosis in lung cancer cells by regulating miR-30a-5p/ADAM19, providing a possible therapeutic strategy for lung cancer patients.

Downregulated miR-203 attenuates IL-beta, IL-6, and TNF-alpha activation in TRAF6-treated human renal mesangial and tubular epithelial cells

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (2)

Circulating microRNAs (miRNAs) are attracting major interest as novel non-invasive biomarkers for human autoimmune diseases including lupus nephritis (LN). A previous study showed that altered miR-203 expression may provide highly diagnostic for systemic lupus erythematosus. However, whether miR-203 is a diagnostic biomarker for LN is still unknown. In the present research, serum samples from 35 cases of active LN patients, 58 cases of inactive LN patients, and 74 cases of healthy volunteers were collected to analyze the expression profiles of miR-203 by qRT-PCR. The serum concentration of complement component 3 (C3) and complement component 4 (C4) was detected using nephelometry method. The expression of inflammatory cytokines, including interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha), were analyzed using enzyme-linked immunosorbent assay (ELISA). The effect of miR-203 overexpression on the TNF receptor associated factor 6 (TRAF6)-induced inflammation of human renal mesangial cells (HRMCs) and human renal tubular epithelial cell line (HK-2) were evaluated. Results showed that miR-203 in serum of active LN patients was significantly down-regulated when compared with serum from inactive LN patients and healthy volunteers. Receiver operating curve (ROC) showed that decreased circulating miR-203 was a significant diagnostic biomarker for active LN patients, with an area under curve (AUC) of 0.974; sensitivity was 85.79%, and specificity was 89.40%. Significant downregulation of C3 and C4, and obvious upregulation of IL-beta, IL-6, and TNF-alpha, was observed in serum of active LN patients. Furthermore, circulating miR-203 expression was positively correlated with the serum concentrations of C3 and C4, and negatively correlated with the serum expression of IL-1 beta, IL-6, and TNF-alpha in active LN patients. In addition, transfection of HRMCs and HK-2 cells with miR-203 mimics could suppress TRAF6-induced IL-beta, IL-6, or TNF-alpha expression compared to cells treated with the mimics control group. In summary, decreased circulating miR-203 might be a candidate diagnostic biomarker for human active LN, and it attenuated IL-beta, IL-6, and TNF-alpha activation in TRAF6-treated HRMCs and HK-2 cells.

Coexistence of micro-inflammatory and macrophage phenotype abnormalities in chronic kidney disease

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (2)

The heterogeneity of macrophages promotes renal fibrosis and plays an important role in the repair of kidney damage. The "microinflammation state" is closely related to accelerated mortality in patients with chronic kidney disease (CKD). The aim of this study was to investigate the relationship between microinflammation and macrophage polarization in CKD. The levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in peripheral blood of 30 non-dialysis CKD-5 patients (CKD group) and 20 healthy subjects (Con group) were measured. Peripheral mononuclear cells (PBMC) of each group were obtained, induced to differentiate into mature macrophages, and the expression of CD206 on the surface of macrophage M2 was detected. The expression of IL-10, TGF-beta 1 and TNF-alpha in the supernatant of macrophage culture medium was detected by real time RCR and ELISA. We found that the levels of hs-CRP, IL-6 and TNF-alpha in peripheral blood of patients with CKD were significantly higher than those of the control group. The expression of CD206 in macrophages was significantly decreased in CKD patients. The anti-inflammatory cytokines IL-10 and TGF-beta 1 in the supernatant of CKD macrophages decreased significantly, while the pro-inflammatory factor TNF-alpha did not change significantly. Our results demonstrate that the expressions of macrophage phenotype and anti-inflammatory cytokine in CKD patients are abnormal, which may be related to the microinflammation state prevalent in CKD patients.

Clinicopathologic significance and treatment of ASC-US in cervical cytology

期刊: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2020; 13 (2)

Background: In China, cervical cancer is one of the most common gynecologic malignancies. Cervical cytology is an essential method for screening cervical cancer and cervical intraepithelial neoplasia (CIN), and the most common cytological abnormality result is atypical squamous cells of undetermined significance (ASC-US). Therefore, how to effectively deal with ASC-US cytology has become the focus of scholars. Objective: We aim to analyze the final histopathologic results, clinicopathologic significance and current rationale of ASC-US cytology. Methods: All patients with first ASC-US cytological reports who attended our gynecological outpatient clinic in Qilu Hospital of Shandong University during January 2010 to December 2015 were recruited to this study. The data were derived from clinical records and evaluated retrospectively. The results of age, High-Risk HPV (DNA) testing, colposcopy, and pathological outcomes were obtained. Directed biopsy was performed if there were any suspicious cervical lesions under colposcopy, while four quadrant biopsy and/or ECC were performed if no suspicious lesions were noted in colposcopies. Results: A total of 1246 patients diagnosed with ASC-US were involved in the final statistical analysis. Mean age of patients was 41.6 years and the age range between 40-49 years represented 38.52% of all ASC-US women in this study. All patients were evaluated for HPV (DNA) and positive percent for High-Risk HPV was (67.1%). Accordingto the final histopathologic outcomes after ASC-US cytology, 15.6% and 1.1% of patients had >= CIN2+ and invasive carcinoma respectively. Patients with invasive carcinoma were associated with HPV16+ and HPV18+. The detection rate of >= CIN2+ among the ASC-US/High-Risk HPV+ group was (53.9%) with a negative-predictive-value (NPV) of 100%. Our findings showed that the final pathologic results of >= CIN2+ were consistent with colposcopy with a coincidence rate of (77%), and colposcopical impression sensitivity and specificity for >= CIN2+ was (91.1% and 96.1%) respectively. Conclusion: Women with ASC-US have a wide range of final pathologic results, and it can be the initial warning of high-grade CIN or cervical cancer. In China, HPV (DNA) testing triage is a useful shunting measure for ASC-US patients, and an immediate colposcopy is a consequential strategy for dealing with ASC-US cytology to increase the detection rate of high-grade cervical lesions or invasive cancer.

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