Development Of Multiple Tumors Research Articles

ОЦЕНКА ВКЛАДА ОБЛУЧЕНИЯ В РАЗВИТИЕ МНОЖЕСТВЕННЫХ ОНКОЛОГИЧЕСКИХ ЗАБОЛЕВАНИЙ В ОТДАЛЕННОМ ПЕРИОДЕ ОСТРОЙ ЛУЧЕВОЙ БОЛЕЗНИ

Purpose: On clinical examples to estimate a probable contribution of the postponed earlier external radiation of all body in the doses exceeding 1 Gy at development of multiple malignant neoplasms of different localization and a leukaemia.
 Material and methods: At 8 of 164 patients, it is long observed after the postponed acute radiation syndrome (ARS), multiple oncological diseases are revealed. Dynamics of consecutive forming of solid tumors at 2 patients and also malignant neoplasms and a myelodysplastic syndrome (MDS) with transformation in an acute leukamia at 1 patient is tracked. Observation duration – 31 years, 43 years and 32 years. 
 Results: Availability of medical care to the patients who transferred ARS and high quality of its rendering at all stages (out-patient, stationary) allowed to reveal malignant neoplasms at early stages of development and to achieve an absolute recovery. However eventually at these patients development and other oncological diseases was observed. The given clinical observations allow to assume that at presented cases radiation acted on various stages of carcinogenesis, and its contribution to development of different oncological diseases in all patients was not identical.
 Conclusion: The analysis of clinical observations allows to assume that radiation contribution to genesis of various oncological diseases at the persons which underwent radiation in the doses causing development of ARS is various. Now in our country there are no approaches to quantitative assessment of a contribution of radiation effects to development of malignant neoplasms in each case. The patients who underwent acute single exposition in doses over 1 Gy have to be considered as having predisposition to development of multiple tumors in the remote terms. In this regard they for life need medical follow up for the purpose of early diagnostics and adequate treatment of the developing malignant neoplasms.

CypA: A Potential Target of Tumor Radiotherapy and/or Chemotherapy.

Cyclophilin A (CypA) is a ubiquitous and highly conserved protein. CypA, the intracellular target protein for the immunosuppressant cyclosporine A (CsA), plays important cellular roles through peptidyl-prolyl cis-trans isomerase (PPIase). Increasing evidence shows that CypA is up-regulated in a variety of human cancers. In addition to being involved in the occurrence and development of multiple tumors, overexpression of CypA has also been shown to be strongly associated with malignant transformation. Surgery, chemotherapy and radiotherapy are the three main treatments for cancer. Chemotherapy and radiotherapy are often used as direct or adjuvant treatments for cancer. However, various side effects and resistance to both chemotherapy and radiotherapy bring great challenges to these two forms of treatment. According to recent reports, CypA can improve the chemosensitivity and/or radiosensitivity of cancers, possibly by affecting the expression of drug-resistant related proteins, cell cycle arrest and activation of the mitogen-activated protein kinase (MAPK) signaling pathways. In this review, we focus on the role of CypA in cancer, its impact on cancer chemotherapeutic and radiotherapy sensitivity, and the mechanism of action. It is suggested that CypA may be a novel potential therapeutic target for cancer chemotherapy and/or radiotherapy.

Antihypertensive Drugs and Cancer: Simultaneously Development of Choroidal Melanoma and Colon Carcinoma after Administration with Valsartan/ Hydrochlorothiazide

Recently published experimental data on the presence of different types of angiotensin receptors in melanoma tissue and in breast cancer, for example, are undoubtedly alarming and indicative because Sartan therapy (in certain groups of patients) may be a risk factor for the patients themselves. The reason for this is the ability of the specific group of drugs to promote carcinogenesis by blocking certain types of receptors, presented in certain types of tumors. The available in vivo and in vitro data in the world literature on the influence of antihypertensive drugs (Sartans and Thiazide diuretics) on melanogenesis and development of other cancerous forms, although disputed, are numerous. Even more disturbing are the further data in the medical literature on the development of multiple tumors after administration of Sartans alone or in combination with hydrochlorothiazide. According to other literature data, even monotherapy with the already mentioned diuretic- hydrochlorothiazide, could be seen as a possible key or risk factor for the development of cutaneous melanoma. We present a clinical case of a 67-year-old patient with anamnestic data for systemic antihypertensive therapy with a combined preparation containing Valsartan / hydrochlorothiazide 160 mg / 12.5 mg for the period from the end of 2011 to March, 2020, came on occasion of a prophylactic dermatological examination. The examination found a pigmented lesion in the right torso, clinically and dermatoscopically suspected of thin cutaneous melanoma. According to the anamnesis and available documentation, it is clear that within this combined antihypertensive medication, the patient has developed two additional neoplasms in the recent past: choroidal melanoma and colorectal carcinoma successfully treated surgically. To what extent, the shared data (on the occurrence of multiple tumors after combination treatment with antihypertensives such as sartans and thiazide diuretics) would lead to the necessary and desirable rethinking of therapeutic strategies for the treatment of hypertension and clarification of the mechanisms at molecular level, at this moment - remains unclear. But in practice it should be highly recommended. Keywords: Melanoma; Melanogenesis; Antihypertensive Therapy; Valsartan; Sartans; Surgery; Hydrochlorothiazide

STIP1 down-regulation inhibits glycolysis by suppressing PKM2 and LDHA and inactivating the Wnt/β-catenin pathway in cervical carcinoma cells

AimsGlycolysis is an important process for cervical carcinoma development. Previous studies have indicated that stress-induced phosphoprotein 1 (STIP1) is associated with development of multiple tumors. Nevertheless, the role and mechanism of STIP1 in glycolysis of cervical carcinoma remain unclear. Main methodsThe association between STIP1 and survival probability and the correlation between STIP1 expression and pyruvate kinase M2 (PKM2) as well as lactate dehydrogenase isoform A (LDHA) levels in cervical carcinoma were analyzed via The Cancer Genome Atlas (TCGA). The expression of STIP1, PKM2, LDHA, and cytochrome c (Cyt C) was measured via western blot or quantitative reverse transcription polymerase chain reaction. Cell viability and apoptosis were examined via cell counting kit 8 and flow cytometry, respectively. Glycolysis was assessed via detection of glucose consumption and lactate production. The protein involved in the Wnt/β-catenin pathway was measured via western blot. Key findingsSTIP1 abundance was elevated in cervical carcinoma cells. High expression of STIP1 indicated poor survival probability. Knockdown of STIP1 inhibited cervical carcinoma cell viability and promoted apoptosis. STIP1 expression was positively correlated with PKM2 and LDHA levels in cervical carcinoma. Silence of STIP1 inhibited glycolysis and decreased PKM2 and LDHA expression. Down-regulation of STIP1 repressed the Wnt/β-catenin pathway. Overexpression of β-catenin reversed the effect of STIP1 silence on viability, apoptosis, glycolysis, and levels of PKM2 and LDHA. SignificanceSTIP1 knockdown suppressed glycolysis in cervical carcinoma by inhibiting PKM2 and LDHA expression and activation of the Wnt/β-catenin pathway.

Orthotopic neobladder after cystectomy for bladder cancer.

More than 90% of bladder cancer is composed of transitional cell carcinoma (TCC), being characterized by the development of multiple tumors in the entire urinary tract over time. When cystectomy is conducted, the urinary tract must be reconstructed by various procedures, which can include an orthotopic neobladder using the patient’s own intestine formed into a spherical shape anastomosed to the urethra. Using this procedure, patients can void urine from their own urethra even after cystectomy. The incidence of subsequent urethral cancer arising after cystectomy is known to be relatively high; however, if patients with a high risk of urethral recurrence are appropriately excluded, a neobladder can be safely provided for patients. Orthotopic neobladder use is reviewed from an oncological viewpoint and the patient’s quality of life after cystectomy for bladder cancer.

MiR‑200b regulates breast cancer cell proliferation and invasion by targeting radixin

Radixin is an important member of the Ezrin-Radixin-Moesin protein family that is involved in cell invasion, metastasis and movement. microRNA (miR)-200b is a well-studied microRNA associated with the development of multiple tumors. Previous bioinformatics analysis has demonstrated that miR-200b has a complementary binding site in the 3'-untranslated region of radixin mRNA. The present study aimed to investigate the role of miR-200b in regulating radixin expression, cell proliferation and invasion in breast cancer. Breast cancer tissues at different Tumor-Node-Metastasis (TNM) stages were collected; breast tissues from patients with hyperplasia were used as a control. miR-200b and radixin mRNA expression levels were tested by reverse transcription-quantitative PCR. Radixin protein expression was detected by western blotting. The highly metastatic MDA-MB-231 cells were divided into four groups and transfected with a miR-negative control (NC), miR-200b mimic, small interfering (si)RNA-NC or siRNA targeting radixin. Cell invasion was evaluated by Transwell assay and cell proliferation was assessed by 5-ethynyl-2'-deoxyuridine staining. Compared with the control group, radixin mRNA expression was significantly higher in breast cancer tissues and increased with TNM stage. miR-200b expression levels exhibited the opposite trend. Radixin mRNA expression in breast cancer cells was notably higher, whereas miR-200b expression was lower compared with that in normal breast epithelial MCF-10A cells. The expression of radixin was higher, whereas miR-200b was lower in MDA-MB-231 cells compared with that in MCF-7 cells. miR-200b mimic or siRNA-radixin transfection downregulated the expression of radixin in MDA-MB-231 cells and attenuated the invasive and proliferative abilities of these cells. miR-200b-knockdown and radixin overexpression were associated with enhanced cell invasion in breast cancer. In conclusion, miR-200b regulates breast cancer cell proliferation and invasion by targeting radixin expression.

Sulforaphene induces apoptosis and inhibits the invasion of esophageal cancer cells through MSK2/CREB/Bcl-2 and cadherin pathway in vivo and in vitro

BackgroundAs a novel type of isothiocyanate derived from radish seeds from cruciferous vegetables, sulforaphene (SFE, 4-methylsufinyl-3-butenyl isothiocyanate) has various important biological effects, such as anti-oxidative and anti-bacterial effects. Recently, sulforaphene has attracted increasing attention for its anti-tumor effects and its ability to suppress the development of multiple tumors through different regulatory mechanisms. However, it has not yet been widely investigated for the treatment of esophageal cancer.MethodsWe observed an increased apoptosis in esophageal cancer cells on sulforaphene treatment through flow cytometry (FCM) analysis and transmission electron microscopy (TEM). Through mass spectrometry (MS) analysis, we further detected global changes in the proteomes and phosphoproteomes of esophageal cancer cells on sulforaphene treatment. The molecular mechanism of sulforaphene was verified by western blot,the effect and mechanism of SFE on esophageal cancer was further verified by patient-derived xenograft mouse model.ResultsWe identified multiple cellular processes that were changed after sulforaphene treatment by proteomics. We found that sulforaphene could repress the phosphorylation of CREB through MSK2, leading to suppression of Bcl-2 and further promoted cell apoptosis. Additionally, we confirmed that sulforaphene induces tumor cell apoptosis in mice. Interestingly, we also observed the obvious inhibition of cell migration and invasion caused by sulforaphene treatment by inhibiting the expression of cadherin, indicating the complex effects of sulforaphene on the development of esophageal cancer.ConclusionsOur data demonstrated that sulforaphene induced cell apoptosis and inhibits the invasion of esophageal cancer through a mechanism involving the inhibition of the MSK2–CREB–Bcl2 and cadherin pathway. Sulforaphene could therefore serve as a promising anti-tumor drug for the treatment of esophageal cancer.

Targeting YAP suppresses ovarian cancer progression through regulation of the PI3K/Akt/mTOR pathway.

Ovarian cancer (OC) is highly metastatic due to frequent peritoneal dissemination, and its treatment poses a major challenge in clinical practice. Yes‑associated protein(YAP) is known to be associated with the development of multiple tumors. However, whether targeting YAP can restrain OC progression and the underlying mechanisms have yet to be fully elucidated. In the present study, YAP was found to be highly expressed in OC, and its expression was correlated with the prognosis of OC patients. Moreover, silencing of YAP markedly inhibited the malignant behavior of OC cells, possibly through regulation of the PI3K/Akt/mTOR pathway. Notably, peptide17, a YAP inhibitor, exerted a significant attenuating effect on OC progression by diminishing the activation of the PI3K/Akt/mTOR pathway invitro as well as invivo. Taken together, these findings demonstrated that targeting YAP attenuated OC progression and suggested the potential application of peptide17 in OC therapy, thus providing new insights into improving the treatment of OC.

SHARPIN overexpression promotes TAK1 expression and activates JNKs and NF-κB pathway in Mycosis Fungoides.

Mycosis Fungoides (MF) is the most common subtype of cutaneous T-cell lymphomas (CTCL). Shank-associated RH domain-interacting protein (SHARPIN) participates in the initiation and development of multiple tumors. However, the clinical significance of SHARPIN in MF hasn't been investigated. The c-Jun N-terminal kinases (JNKs) pathway is a member of mitogen-activated protein kinases (MAPKs). Its dysregulation is observed in various tumors including CTCL, whereas the roles of JNKs pathway in MF remain largely unknown, the relationship between SHARPIN and JNKs pathway remains elusive. Herein, we showed that upregulated expression of SHARPIN was related to poor prognosis of MF patients. In vitro experiments found increased SHARPIN expression and activation of JNKs pathway in MF cell line MyLa2059. SHARPIN induced transforming growth factor β activated kinase-1 (TAK1) transcription, which is an upstream kinase of JNKs, NF-κB and p38 pathway, leading to activation of JNKs and NF-κB pathway. SHARPIN also promoted p38 signalling independent of TAK1 expression, by which overexpression of SHARPIN induced cell proliferation, inhibited apoptosis, enhanced migration and invasion of MyLa2059. Our work provided direct evidences for effects of SHARPIN on JNKs and NF-κB pathway, and the contributing roles of JNKs, NF-κB and p38 pathway regulated by SHARPIN in the development of MF.

MiR-143-3p suppresses the progression of nasal squamous cell carcinoma by targeting Bcl-2 and IGF1R

Dysregulated microRNAs (miRNAs) play crucial roles in the occurrence and development of multiple tumours, but their roles in the progression of nasal squamous cell carcinoma (NSCC) remain unknown. The aim of our study was to investigate the potential function and molecular mechanism of miR-143-3p in NSCC. Expression of miRNA and mRNA was detected by quantitative real-time reverse transcription-PCR (qRT-PCR). Forced overexpression of miR-143-3p was established by transfecting mimics into NSCC cell line. Then, we investigated the role of miR-143-3p in human NSCC cell proliferation, apoptosis, cycle and migration by using MTT, flow cytometry and transwell assays. Bioinformatics analysis, qRT-PCR, Western blot and luciferase reporter analysis were performed to validate the relationship between miR-143-3p and its potential targets. We found that miR-143-3p was substantially downregulated in human NSCC tissues and cell line. Forced upregulation of miR-143-3p significantly attenuated cell proliferation and migration. Furthermore, this change could induce apoptosis and G1-phase arrest of NSCC cells. Mechanistically, miR-143-3p directly targeted and significantly suppressed Bcl-2 and IGF1R expression. In summary, miR-143-3p regulation of the proliferation, apoptosis, cell cycle and migration of NSCC probably partly depends on inhibition of Bcl-2 and IGF1R, indicating that miR-143-3p may be a novel molecular therapeutic target for NSCC.

High relative levels of satellite alpha transcripts predict increased risk of bilateral breast cancer and multiple primary cancer in patients with breast cancer and lacking BRCA‑related clinical features

Patients with breast cancer who undergo surgery have a risk of developing multiple cancers in the contralateral breast and other organs. We previously reported that overexpression of satellite alpha transcripts (SAT) facilitates chromosomal instability, which is involved in the development of multiple tumors in patients with colorectal and gastric cancer. In this study, we elucidated the significance of SAT in the development of multiple tumors in patients with breast cancer. Relative expression of SAT (rSAT) was calculated in normal and tumor tissues from 167 patients. In total, 27 patients developed bilateral breast cancer (BBC) and 27 patients showed multiple primary cancer (MPC), with patients with BBC and MPC showing higher rSAT levels in tumor tissues than those in patients with single breast cancer (SBC) (P=0.0312 and P=0.0420, respectively). Additionally, higher rSAT levels in tumor tissues from patients with BBC were a significant factor according to univariate analysis, and multivariate analysis showed that rSAT >1.5 was a significant predictor of MPC [hazard ratio (HR): 2.96; P=0.0243); however, we did not clarify the involvement of SAT in normal tissues. Excluding 71 patients with BRCA‑related clinical features, rSAT levels were higher in patients with BBC and MPC than in patients with SBC in tumor tissues and normal tissues (P<0.05). Significant predictors according to univariate analysis included rSAT >1.5 in tumor tissues, rSAT >2.4 in normal tissues, and T <2, whereas those for multivariate analysis included rSAT >2.4 in normal tissues for BBC (HR: 22.7; P=0.00120) and MPC (HR: 13.0; P=0.00601). Our data indicated that patients with breast cancer and high rSAT levels in their breast tissues exhibit a 10‑ to 20‑fold increased risk for the development of multiple cancers when harboring no BRCA‑related clinical features.

MiR-199a-3p inhibition facilitates cardiomyocyte differentiation of embryonic stem cell through promotion of MEF2C.

MicroRNAs (miRNAs) is a small molecule (19-25 nucleotide) noncoding RNA that inhibits the expression of target messenger RNA (mRNA) at the posttranscriptional level as an endogenous regulator. There is an increasing evidence that miR-199a-3p has a significant effect on the development of multiple tumors. However, the specific roles of miR-199a-3p in myocardial differentiation of embryonic stem cell still need to be investigated. Method of the hanging drop was used to build the model of cardiomyocyte differentiation of stem cell and beating rate of embryoid bodies (EBs) was calculated. The levels of intracellular MEF2C, a-MHC, GATA4, Nkx2.5, and cTnT mRNA were measured by real-time quantitative polymerase chain reaction, while the expressions of miR-199a-3p were detected simultaneously. Protein levels of MEF2C, a-MHC, GATA4, Nkx2.5, and cTnT were quantified by western blot analysis. Immunoreactivities of MEF2C and cTnT were analyzed by immunofluorescence. The interaction between miR-199a-3p and its predicted target (3'-untranslated region of MEF2C mRNA) was verified by luciferase assay. MiR-199a-3p levels increased during cardiogenesis. MiR-199a-3p inhibitor increased the beating rate of EBs and promoted expressions of cardiac-specific markers (GATA4, Nkx2.5, cTnT, and a-MHC). Notably, miR-199a-3p inhibition brought upregulation of MEF2C, which is the target of miR-199a-3p that we predicted and verified experimentally. In addition, MEF2C siRNA decreased miR-199a-3p inhibitor promoted EBs beating and attenuated miR-199a-3p inhibitor-induced cTnT and MEF2C expressions. The results above showed that MEF2C was involved in the process of promoting the differentiation of stem cells into cardiac myocytes by miR-199a-3p inhibitors.

Satellite alpha transcript levels to predict risk of bilateral breast cancer and multiple primary cancer in patients with breast cancer who lack BRCA-related clinical features.

e12575 Background: Patients with breast cancer who undergo surgery have a risk of developing multiple cancers in the contralateral breast and other organs. We have reported that the overexpression of satellite alpha transcripts (SAT) facilitates chromosomal instability, which is involved in the development of multiple tumors in patients with colorectal and gastric cancer. Methods: In this study, we elucidated the significance of SAT in the development of multiple tumors in patients with breast cancer. Relative expression SAT (rSAT) level was calculated in normal and tumor tissues from 167 patients. Twenty-seven patients developed bilateral breast cancer (BBC) and 27 patients showed multiple primary cancer (MPC). We detected that 71 patients had factors associated with inherited breast cancer; age under 50yo, harboring family history of breast cancer, pathological diagnosis of TNBC, and history of ovarian cancer and we determined these factors as BRCA-related clinical factors. Results: We excluded 71 patients with BRCA-related clinical features, rSAT levels were higher in patients with BBC and MPC than in patients with SBC in tumor tissues ( P = 0.0121) and normal tissues ( P = 0.00586). A univariate analysis indicated significant predictors including rSAT &gt; 1.5 in tumor tissues, rSAT &gt; 2.4 in normal tissues. In a multivariate analysis, rSAT &gt; 2.4 in normal tissues was a significant predictor of BBC (HR, 22.7; P = 0.00120) and MPC (HR, 11.1; P = 0.00885). Conclusions: Our data indicated that patients with breast cancer with high rSAT levels in their breast tissues have a 10- to 20-fold increased risk for the development of multiple cancers when they harbored no BRCA-related clinical features. These patients had been excluded from the high-risk group for BBC, however, our results shed light on these patients and we detected another risk factor which could predict multiple cancers.

NUMB knockdown enhanced the anti-tumor role of cisplatin on ovarian cancer cells by inhibiting cell proliferation and epithelial-mesenchymal transition.

BackgroundNUMB is an inhibitory regulator of NOTCH signaling, which is critical for the induction of epithelial-mesenchymal transition (EMT). Loss of NUMB expression is correlated with the genesis and development of multiple tumors. Recent studies reported that NUMB expression was upregulated in human ovarian cancer. However, the role of NUMB in ovarian cancer is still unclear. Here, we invested the effect of NUMB knockdown on the proliferation and EMT in ovarian cancer cells and explored the role of NUMB in the effect of cisplatin.MethodsTwo ovarian cancer cells (OVCAR-3 and SK-OV-3) were used in the experiments. The proliferation and apoptosis of ovarian cancer cells was examined using methyl thiazolyl tetrazolium (MTT) test and flow cytometry assays. The invasion and migration of ovarian cancer cells were examined using Transwell assays. The expression of EMT markers were examined using Simple Western analysis.ResultsNUMB knockdown inhibited cell proliferation, invasion, and migration in both ovarian cancer cells. NUMB knockdown enhanced cisplatin-induced cell growth inhibiting and apoptosis in both ovarian cancer cells. NUMB knockdown enhanced cisplatin-induced cell invasion in SK-OV-3 cells. NUMB knockdown also decreased the expression of N-cadherin and Vimentin in SK-OV-3 cells.ConclusionsNUMB acted as an oncogene in ovarian cancer and NUMB knockdown enhanced the anti-tumor role of cisplatin on ovarian carcinoma cells by inhibiting cell proliferation and EMT.

MRTF-A Regulates the Proliferation and Migration of Non-small Cell Lung Cancer Cells of A549 through HOTAIR

背景与目的非小细胞肺癌（non-small cell lung cancer, NSCLC）作为肺癌的一种，由于其高发病率一直备受关注。准确揭示其发病机制对于NSCLC的诊断以及治疗具有重要的指导意义。MATF-A作为转录调控因子在多种肿瘤的发生发展过程中发挥着重要作用，可以调控多种肿瘤细胞的迁移过程。HOTAIR是近年研究发现的一个长链非编码RNA，在多种肿瘤中异常表达并参与多种肿瘤的增殖及迁移的进程。本研究旨在探究MRTF-A通过HOTAIR调控NSCLC的增殖及迁移进程。方法构建MRTF-A的过表达质粒及干扰质粒，检测对A549细胞增殖及迁移的影响。设计合成HOTAIR的siRNA检测对A549细胞增殖及迁移的作用。qRT-PCR检测MRTF-A对HOTAIR表达的调控作用。构建HOTAIR的启动子检测MRTF-A对HOTAIR启动子活性的影响。结果过表达MRTF-A促进A549细胞的增殖，沉默MRTF-A的表达抑制A549细胞的增殖及迁移。干扰HOTAIR的表达抑制A549细胞的增殖及迁移。MRTF-A能够影响HOTAIR的表达，同时能够调控HOTAIR启动子的活性。结论MRTF-A通过HOTAIR调控NSCLCA549细胞的增殖及迁移进程。

NUMB knockdown enhanced the anti-tumor role of cisplatin on ovarian cancer cells by inhibiting cell proliferation and epithelial-mesenchymal transition

Background: NUMB is an inhibitory regulator of NOTCH signaling, which is critical for the induction of epithelial-mesenchymal transition (EMT). Loss of NUMB expression is correlated with the genesis and development of multiple tumors. Recent studies reported that NUMB expression was upregulated in human ovarian cancer. However, the role of NUMB in ovarian cancer is still unclear. Here, we invested the effect of NUMB knockdown on the proliferation and EMT in ovarian cancer cells and explored the role of NUMB in the effect of cisplatin. Methods: Two ovarian cancer cells (OVCAR-3 and SK-OV-3) were used in the experiments. The proliferation and apoptosis of ovarian cancer cells was examined using methyl thiazolyl tetrazolium (MTT) test and flow cytometry assays. The invasion and migration of ovarian cancer cells were examined using Transwell assays. The expression of EMT markers were examined using Simple Western analysis. Results: NUMB knockdown inhibited cell proliferation, invasion, and migration in both ovarian cancer cells. NUMB knockdown enhanced cisplatin-induced cell growth inhibiting and apoptosis in both ovarian cancer cells. NUMB knockdown enhanced cisplatin-induced cell invasion in SK-OV-3 cells. NUMB knockdown also decreased the expression of N-cadherin and Vimentin in SK-OV-3 cells. Conclusions: NUMB acted as an oncogene in ovarian cancer and NUMB knockdown enhanced the anti-tumor role of cisplatin on ovarian carcinoma cells by inhibiting cell proliferation and EMT.

MiR-183-5p Inhibits Occurrence and Progression of Acute Myeloid Leukemia via Targeting Erbin.

Erbin has been shown to have significant effects on the development of solid tumors. However, little is known about its function and regulatory mechanism in hematological malignancies. The biological function of Erbin on cell proliferation was measured in vitro and in vivo. The predicted target of Erbin was validated by dual-luciferase reporter assay and rescue experiment. We found that overexpression of Erbin could inhibit the cell proliferation and promote the cell differentiation of acute myeloid leukemia (AML) cells, whereas depletion of Erbin could enhance the cell proliferation and block the cell differentiation in AML cells in vitro and in vivo. Besides, miR-183-5p was identified as the upstream regulator that negatively regulated the Erbin expression. The results were confirmed by dual-luciferase reporter and RNA pull-down assay. Furthermore, we found that miR-183-5p negatively regulated Erbin, resulting in enhanced cell proliferation of AML cells via activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways. The activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways was mediated by Erbin interacting with Grb2. These results were also validated by rescue experiments in vitro and in vivo. All above-mentioned findings indicated that the miR-183-5p/Erbin signaling pathway might represent a novel prognostic biomarker or therapeutic target for treatment of AML.

Asymmetrical proliferative pattern loss linked to cyclin D1 overexpression in adjacent non-tumour epithelium in oral squamous cell carcinoma

ObjectiveTo evaluate cyclin D1 overexpression in oral squamous cell carcinomas and adjacent non-tumour epithelium as a biomarker of premalignant fields and a risk factor for multiple tumour development. DesignWe studied cyclin D1 expression in 54 patients with 68 oral squamous cell carcinomas plus adjacent non-tumour epithelia characterized as close (n = 58) or distant (n = 41) from the invasion point. Randomized 40x fields were evaluated (4 in tumour tissue and 1 each in close and distant non-tumour epithelium). Expression in non-tumour epithelium was evaluated in basal, parabasal, middle-third and upper-third compartments. ResultsCyclin D1 overexpression was found in both carcinomas and non-tumour epithelia. Nuclear expression in basal and parabasal layers of distant epithelium was significantly increased in patients with multiple tumours (p < 0.001). A significant association between cyclin D1 overexpression in different epithelial layers was found in both close and distant epithelia. A significant association was found between nuclear expressions of cyclin D1 and Ki-67 in the basal layer of distant epithelium (p = 0.02). ConclusionsCyclin D1 overexpression is an early event in oral carcinogenesis linked to loss of the physiological asymmetrical proliferation pattern. Cyclin D1 overexpression in basal and parabasal layers of epithelia distant from the invasion point may act as a potential marker of premalignant fields and multiple tumour development.

Risk of multiple colorectal cancer development depends on age and subgroup in individuals with hereditary predisposition.

Development of multiple colorectal cancers (CRCs), synchronously or metachronously, is associated with hereditary predisposition for cancer and accurate risk estimates of multiple tumour development are relevant to recommend rational surveillance programs. A cross-sectional study design was used to estimate the risks of synchronous CRC (SCRC) and metachronous CRC (MCRC) based on data from the National Danish Hereditary Nonpolyposis Register. In total, 7100 individuals from families within the subgroups Lynch syndrome, familial CRC (FCC) and moderate risk were used with estimates relative to a non-hereditary population control cohort. SCRC was diagnosed in 7.4% of the Lynch syndrome cases, in 4.2% of FCC cases and 2.5% of the moderate risk cases, which translated to relative risks of 1.9-5.6. The risk of MCRC was distinctively linked to Lynch syndrome with a life-time risk up to 70% and an incidence rate ratio of 5.0. The risk of SCRC was significantly increased in all subgroups of FCC and hereditary CRC, whereas the risk of MCRC was specifically linked to Lynch syndrome. These observations suggest that individuals with FCC or hereditary CRC should be carefully screened for second primary CRC at the time of diagnosis, whereas intensified surveillance for second primary CRC is motivated in Lynch syndrome with lower-intensity programs in families with yet unidentified genetic causes.

The MST4–MOB4 complex disrupts the MST1–MOB1 complex in the Hippo–YAP pathway and plays a pro-oncogenic role in pancreatic cancer

The mammalian STE20-like protein kinase 1 (MST1)-MOB kinase activator 1 (MOB1) complex has been shown to suppress the oncogenic activity of Yes-associated protein (YAP) in the mammalian Hippo pathway, which is involved in the development of multiple tumors, including pancreatic cancer (PC). However, it remains unclear whether other MST-MOB complexes are also involved in regulating Hippo-YAP signaling and have potential roles in PC. Here, we report that mammalian STE20-like kinase 4 (MST4), a distantly related ortholog of the MST1 kinase, forms a complex with MOB4 in a phosphorylation-dependent manner. We found that the overall structure of the MST4-MOB4 complex resembles that of the MST1-MOB1 complex, even though the two complexes exhibited opposite biological functions in PC. In contrast to the tumor-suppressor effect of the MST1-MOB1 complex, the MST4-MOB4 complex promoted growth and migration of PANC-1 cells. Moreover, expression levels of MST4 and MOB4 were elevated in PC and were positively correlated with each other, whereas MST1 expression was down-regulated. Because of divergent evolution of key interface residues, MST4 and MOB4 could disrupt assembly of the MST1-MOB1 complex through alternative pairing and thereby increased YAP activity. Collectively, these findings identify the MST4-MOB4 complex as a noncanonical regulator of the Hippo-YAP pathway with an oncogenic role in PC. Our findings highlight that although MST-MOB complexes display some structural conservation, they functionally diverged during their evolution.