Evaluation of Doxorubicin-loaded Echogenic Macroemulsion for Targeted Drug Delivery.

BACKGROUND: The latest technology trend in targeted drug delivery highlights stimuliresponsive particles that can release an anticancer drug in a solid tumor by responding to external stimuli. OBJECTIVE: This study aims to design, fabricate, and evaluate an ultrasound-responsive drug delivery vehicle for an ultrasound-mediated drug delivery system. METHODS: The drug-containing echogenic macroemulsion (eME) was fabricated by an emulsification method using the three phases (aqueous lipid solution as a shell, doxorubicin (DOX) contained oil, and perfluorohexane (PFH) as an ultrasound-responsive agent). The morphological structure of eMEs was investigated using fluorescence microscopy, and the size distribution was analyzed by using DLS. The echogenicity of eME was measured using a contrast-enhanced ultrasound device. The cytotoxicity was evaluated using a breast cancer cell (MDA-MB-231) via an in vitro cell experiment. RESULTS: The obtained eME showed an ideal morphological structure that contained both DOX and PFH in a single particle and indicated a suitable size for enhancing ultrasound response and avoiding complications in the blood vessel. The echogenicity of eME was demonstrated via an in vitro experiment, with results showcasing the potential for targeted drug delivery. Compared to free DOX, enhanced cytotoxicity and improved drug delivery efficiency in a cancer cell were proven by using DOX-loaded eMEs and ultrasound. CONCLUSION: This study established a platform technology to fabricate the ultrasound-responsive vehicle. The designed drug-loaded eME could be a promising platform with ultrasound technology for targeted drug delivery.

Fabrication and Evaluation of Ultrasound-Responsive Emulsion Loading Paclitaxel for Targeted Chemotherapy.

Chemotherapy is the most widely used cancer treatment, but it has several drawbacks such as adverse side effects and low bioavailability. To address these limitations, various drug delivery systems have been investigated, including liposomes, micelles, and emulsions. These drug delivery technologies have been improving the efficacy and safety of conventional chemotherapy. This study presents an emerging drug delivery technology for targeted chemotherapy using drug-loaded ultrasound-responsive emulsion (URE) as a drug carrier and ultrasound technology for external activation. URE was designed to be responsive to ultrasound energy and fabricated by using an emulsification technique. To investigate this technology, paclitaxel, as a model drug, was used and encapsulated into URE. The size distribution, morphology, and drug release behavior of paclitaxel-loaded URE (PTX-URE) were characterized, and the echogenicity of PTX-URE was assessed by using ultrasound imaging equipment. The cellular uptake and cytotoxicity of PTX-URE with ultrasound were evaluated in breast cancer cells (MDA-MB-231). Our in vitro results indicate that the combination of PTX-URE and ultrasound significantly enhanced cellular uptake by 10.6-fold and improved cytotoxicity by 24.1% compared to PTX alone. These findings suggest that the URE platform combined with ultrasound is a promising technology to improve the drug delivery efficiency for chemotherapy.

Multi-MicroRNA Analysis Can Improve the Diagnostic Performance of Mammography in Determining Breast Cancer Risk.

The objective of this study was to determine whether multi-microRNA analysis using a combination of four microRNA biomarkers (miR-1246, 202, 21, and 219B) could improve the diagnostic performance of mammography in determining breast cancer risk by age group (under 50 vs. over 50) and distinguish breast cancer from benign breast diseases and other cancers (thyroid, colon, stomach, lung, liver, and cervix cancers). To verify breast cancer classification performance of the four miRNA biomarkers and whether the model providing breast cancer risk score could distinguish between benign breast disease and other cancers, the model was verified using nonlinear support vector machine (SVM) and generalized linear model (GLM) and age and four miRNA qRT-PCR analysis values (dCt) were input to these models. Breast cancer risk scores for each Breast Imaging-Reporting and Data System (BI-RADS) category in multi-microRNA analysis were analyzed to examine the correlation between breast cancer risk scores and mammography categories. We generated two models using two classification algorithms, SVM and GLM, with a combination of four miRNA biomarkers showing high performance and sensitivities of 84.5% and 82.1%, a specificity of 85%, and areas under the curve (AUCs) of 0.967 and 0.965, respectively, which showed consistent performance across all stages of breast cancer and patient ages. The results of this study showed that this multi-microRNA analysis using the four miRNA biomarkers was effective in classifying breast cancer in patients under the age of 50, which is challenging to accurately diagnose. In addition, breast cancer and benign breast diseases can be classified, showing the possibility of helping with diagnosis by mammography. Verification of the performance of the four miRNA biomarkers confirmed that multi-microRNA analysis could be used as a new breast cancer screening aid to improve the accuracy of mammography. However, many factors must be considered for clinical use. Further validation with an appropriate screening population in large clinical trials is required. This trial is registered with (KNUCH 2022-04-036).

MUC1 expressing tumor growth was retarded after human mucin 1 (MUC1) plasmid DNA immunization.

INTRODUCTION: Naked DNA is one of the attractive tools for vaccination studies. We studied naked DNA vaccination against the human tumor antigen, mucin, which is encoded by the MUC1 gene. METHODS: We constructed the pcDNA3.0-MUC1 (pcDNA-MUC1) plasmid expressing an underglycosylated MUC1 protein. BALB/c mice were immunized intradermally thrice at 2-weeks intervals with pcDNA-MUC1. Two weeks after the last immunization, tumor challenge experiments were performed using either the CT26 or TA3HA tumor cell lines, both of which transduce human MUC1. RESULTS: Immune cell population monitoring from pcDNA-MUC1-immunized animals indicated that immune cell activation was induced by MUC1-specific immunization. Using intracellular fluorescence activated cell sorting and enzyme-linked immunosorbent spot assay, we reported that interferon-γ secreting CD8+ T cells were mainly involved in MUC1-specific immunization. In all mice immunized with MUC1 DNA, tumor growth inhibition was observed, whereas control mice developed tumors (p < 0.001). CONCLUSION: Our results suggest that intradermal immunization with MUC1 DNA induces MUC1-specific CD8+ T cell infiltration into tumors, elicits tumor-specific Th1-type immune response, and inhibits tumor growth.

Multiple biomarkers are more accurate than a combination of carbohydrate antigen 125 and human epididymis protein 4 for ovarian cancer screening.

OBJECTIVE: The objective of this study was to compare and evaluate the diagnostic value of serum carbohydrate antigen 125 (CA125) and/or human epididymis protein 4 (HE4) and a panel of novel multiple biomarkers in patients with ovarian tumors to identify more accurate and effective markers for screening ovarian cancer. METHODS: Candidate ovarian cancer biomarkers were selected based on a literature search. Dozens of candidate biomarkers were examined using 143 serum samples from patients with ovarian cancer and 157 healthy serum samples as noncancer controls. To select the optimal marker panel for an ovarian cancer classification model, a set of biomarker panels was created with the number of possible combinations of eight biomarkers. Using the set of biomarkers as an input variable, the optimal biomarker panel was selected by examining the performance of the biomarker panel set using the Random Forest algorithm as a non-linear classification method and a 10-fold cross-validation technique. RESULTS: The final selected optimal combination of five biomarkers (CA125, HE4, cancer antigen 15-3, apolipoprotein [Apo] A1, and ApoA2) exhibited a sensitivity of 93.71% and specificity of 93.63% for ovarian cancer detection during validation. CONCLUSION: Combining multiple biomarkers is a valid strategy for ovarian cancer diagnosis and can be used as a minimally invasive screening method for early ovarian cancer. A panel of five optimal biomarkers, including CA125 and HE4, was verified in this study. These can potentially be used as clinical biomarkers for early detection of ovarian cancer.

SOCS1 counteracts ROS-mediated survival signals and promotes apoptosis by modulating cell cycle to increase radiosensitivity of colorectal cancer cells.

As negative regulators of cytokine signaling pathways, suppressors of cytokine signaling (SOCS) proteins have been reported to possess both pro-tumor and anti-tumor functions. Our recent studies have demonstrated suppressive effects of SOCS1 on epithelial to mesenchymal signaling in colorectal cancer cells in response to fractionated ionizing radiation or oxidative stress. The objective of the present study was to determine the radiosensitizing action of SOCS1 as an anti-tumor mechanism in colorectal cancer cell model. In HCT116 cells exposed to ionizing radiation, SOCS1 over-expression shifted cell cycle arrest from G2/M to G1 and promoted radiation-induced apoptosis in a p53-dependent manner with down-regulation of cyclin B and up-regulation of p21. On the other hand, SOCS1 knock-down resulted in a reduced apoptosis with a decrease in G1 arrest. The regulatory action of SOCS1 on the radiation response was mediated by inhibition of radiation-induced Jak3/STAT3 and Erk activities, thereby blocking G1 to S transition. Radiation-induced early ROS signal was responsible for the activation of Jak3/Erk/STAT3 that led to cell survival response. Our data collectively indicate that SOCS1 can promote radiosensitivity of colorectal cancer cells by counteracting ROS-mediated survival signal, thereby blocking cell cycle progression from G1 to S. The resulting increase in G1 arrest with p53 activation then contributes to the promotion of apoptotic response upon radiation. Thus, induction of SOCS1 expression may increase therapeutic efficacy of radiation in tumors with low SOCS1 levels. [BMB Reports 2022; 55(4): 198-203].

Sonophoresis with ultrasound-responsive liquid-core nuclei for transdermal drug delivery.

BACKGROUND: Sonophoresis can increase the delivery efficiency of various drugs into the skin. A recent advance in sonophoresis is the use of ultrasound-responsive liquid-core nuclei (URLN) to increase the probability of cavitation. In this study, we developed a URLN and ultrasound device, and demonstrated its effectiveness through in vitro and clinical tests. MATERIALS AND METHODS: Three types of experiments were designed to evaluate the efficiency of sonophoresis with URLN. First, a Franz diffusion cell with cosmetic ingredients was used to analyze quantitatively the amount of drug delivered to the porcine skin. Second, after the application of sonophoresis with URLN, the porcine skin surface was examined using scanning electron microscopy (SEM) to see the changes in morphology. Finally, a clinical test was performed to verify the utility of sonophoresis with URLN. RESULTS: The results indicate that sonophoresis with URLN can increase the amount of compound delivered by approximately 11.9-fold over 6 h for niacinamide and by 7.33-fold over 6 h for adenosine. In addition, we observed approximately 20-30 µm sized pores on porcine skin in SEM images. In clinical testing, the application of sonophoresis with cosmetics containing URLN for 3 min improved the efficiency of transdermal drug delivery by 1.9-fold, the depth of absorption by 2.0-fold, and the speed of absorption by 2.0-fold at 30 min after application. CONCLUSION: We expect that sonophoresis with specialized URLN in transdermal drug delivery could be used widely for various skin-related applications.

Association between erythema nodosum/ erythema induratum of Bazin and Mycobacterium tuberculosis infection in Koreans.

BACKGROUND: Erythema nodosum and erythema induratum of Bazin are similar inflammatory diseases of the lower extremities. These are clinically distinguishable entities, though overlap can occur. Both diseases are reported to be related to Mycobacterium tuberculosis infection, but it is very difficult to identify Mycobacterium tuberculosis in skin lesions. AIM: This study aimed to develop a new nested polymerase chain reaction targeting the IS6110 insertion sequence of M. tuberculosis to improve the M. tuberculosis detection rate in skin lesions of erythema nodosum or erythema induratum of Bazin. METHODS: From May 2016 to Jan 2018, 14 patients with clinically suspicious erythema nodosum or erythema induratum were enrolled in the study. Two cases were classified as erythema nodosum and 12 as erythema induratum. Individual patients were subjected to a 4-mm punch biopsy, and their venous whole blood was sampled immediately after diagnosis. RESULTS: Eight patients were tested for M. tuberculosis using QuantiFERON, of which seven (87.5%) were positive. IS6110-nested polymerase chain reaction on all 14 patients identified 11 (78.6%) positive cases. Four of the eight (50%) individuals tested with QuantiFERON were also positive in the IS6110 nested polymerase chain reaction. The difference between the outcomes of the QuantiFERON and the IS6110-nested polymerase chain reaction tests was not statistically significant. There was also no significant agreement between the results of both assays. Sequencing the IS6110-nested polymerase chain reaction products showed a 97%-100% nucleotide sequence identity with the H37Rv genome. CONCLUSION: It is important to test for tuberculosis in patients with multiple tender subcutaneous nodules on their lower extremities in high-burden tuberculosis countries like Korea. LIMITATIONS: We need to register more suspicious patients to verify the association between erythema nodosum/erythema induratum of Bazin and M. tuberculosis. Furthermore, it is necessary to improve the more sensitive polymerase chain reaction technique to identify M. tuberculosis directly in cutaneous lesions.

Diagnostic value of combining tumor and inflammatory biomarkers in detecting common cancers in Korea.

BACKGROUND: The ultimate goal of cancer screening is to diagnose invasive cancers early, while they are still curable. We aimed to validate the diagnostic value of blood-derived protein biomarkers that we developed for six common cancer in Korea. METHODS: We have discovered 12 protein biomarkers that are useful in differentiating cancer patients from healthy controls using two-dimensional gel electrophoresis (2-DE), surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS), and literature review. Cancer patients (stomach, colon, liver, lung, breast, and prostate) and control subjects were collected and tested data sets were used to generate predictive models that identify risk scores for each cancer. The validation study was done in serum samples of an independent patient cohort Receiver operating characteristic (ROC) analyses were conducted to evaluate the diagnostic performance of the biomarkercombinations. RESULTS: The AUCs of the model in the test set were 0.971, 0.960, 0.969, 0.942, 0.834, and 0.985 for stomach, colon, liver, lung, breast, and prostate cancer, respectively. CONCLUSIONS: Combining multiple tumor and systemic inflammatory biomarkers proved to be a valid strategy in the diagnosis of six common cancers in Korea. Further validation of appropriate screening populations through large-scale clinical trials are warranted.

Multiple microRNAs as biomarkers for early breast cancer diagnosis.

MicroRNA (miRNA or miR) is stably present in plasma. It has been reported that miRNA could be used for detecting cancer. Circulating miRNAs are being increasingly recognized as powerful biomarkers in a number of different pathologies, including in breast cancer. The aim of the current study was to establish and validate miRNA sets that are useful for the early diagnosis of breast cancer. Specifically, the current study intended to determine whether miRNA biomarkers were tumor-specific and to statistically verify whether circulating miRNA analysis could be used for breast cancer diagnosis. In the present study, a total of nine candidate miRNA biomarkers were selected by examining reference miRNAs associated with the generation and progression of breast cancer to identify novel miRNAs that could be used to detect early breast cancer. A total of 226 plasma samples from patients with breast cancer were used. In addition, 146 plasma healthy samples were used as non-cancer controls. These samples were divided into training and validation cohorts. The training cohort was used to identify a combination of miRNA that could detect breast cancer. The validation cohort was used to validate this combination of miRNA. Total RNAs were isolated from collected samples. A total of 9 miRNAs were quantified using reverse-transcription quantitative PCR. A total of nine candidate miRNA expression levels were compared between patients with breast cancer and healthy controls. It was indicated that combinations of two or more of the nine miRNAs could detect breast cancer with higher accuracy than the use of a single biomarker. As a representative example, combinations of four miRNAs (miR-1246+miR-206+miR-24+miR-373) of the nine miRNAs had a sensitivity of 98%, a specificity of 96% and an accuracy of 97% for breast cancer detection in the validation cohort. The results of the present study suggest that multiple miRNAs could be used as potential biomarkers for early diagnosis of breast cancer. These biomarkers are expected to overcome limitations of mammography when used as an auxiliary diagnosis of mammography.

Evaluation of the Value of Multiplex MicroRNA Analysis as a Breast Cancer Screening in Korean Women under 50 Years of Age with a High Proportion of Dense Breasts.

This study was conducted to confirm the performance of the microRNA (miRNA) biomarker combination as a new breast cancer screening method in Korean women under the age of 50 with a high percentage of dense breasts. To determine the classification performance of a set of miRNA biomarkers (miR-1246, 202, 21, and 219B) useful for breast cancer screening, we determined whether there was a significant difference between the breast cancer and healthy control groups through box plots and the Mann-Whitney U-test, which was further examined in detail by age group. To verify the classification performance of the 4 miRNA biomarker set, 4 classification methods (logistic regression, random forest, XGBoost, and generalized linear model plus random forest) were applied, and 10-fold cross-validation was used as a validation method to improve performance stability. We confirmed that the best breast cancer detection performance was achievable in patients under 50 years of age when the set of 4 miRNAs were used. Under the age of 50, the 4 miRNA biomarkers showed the highest performance with a sensitivity of 85.29%, specificity of 93.33%, and area under the curve (AUC) of 0.961. Examining the results of 4 miRNA biomarkers was found to be an effective strategy for diagnosing breast cancer in Korean women under 50 years of age with dense breasts, and hence has the potential as a new breast cancer screening tool. Further validation in an appropriate screening population with large-scale clinical trials is required.

Anti-Amnesic Effect of Walnut via the Regulation of BBB Function and Neuro-Inflammation in Aß1-42-Induced Mice.

This study was conducted to assess the protective effect of walnut (Juglans regia L.) extract on amyloid beta (Aß)1-42-induced institute of cancer research (ICR) mice. By conducting a Y-maze, passive avoidance, and Morris water maze tests with amyloidogenic mice, it was found that walnut extract ameliorated behavioral dysfunction and memory deficit. The walnut extract showed a protective effect on the antioxidant system and cholinergic system by regulating malondialdehyde (MDA) levels, superoxide dismutase (SOD) contents, reduced glutathione (GSH) contents, acetylcholine (ACh) levels, acetylcholinesterase (AChE) activity, and protein expression of AChE and choline acetyltransferase (ChAT). Furthermore, the walnut extract suppressed Aß-induced abnormality of mitochondrial function by ameliorating reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP contents. Finally, the walnut extract regulated the expression of zonula occludens-1 (ZO-1) and occludin concerned with blood-brain barrier (BBB) function, expression of tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), phosphorylated c-Jun N-terminal kinase (p-JNK), phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (p-IκB), cyclooxygenase-2 (COX-2), and interleukin 1 beta (IL-1ß), related to neuroinflammation and the expression of phosphorylated protein kinase B (p-Akt), caspase-3, hyperphosphorylation of tau (p-tau), and heme oxygenase-1 (HO-1), associated with the Aß-related Akt pathway.

Biomarker Panel for the Diagnosis of Pancreatic Ductal Adenocarcinoma.

A single tumor marker has a low diagnostic value in pancreatic cancer. Combinations of multiple biomarkers and unique analysis algorithms can be applied to overcome these limitations. This study sought to develop diagnostic algorithms using multiple biomarker panels and to validate their performance in the diagnosis of pancreatic ductal adenocarcinoma (PDAC). We used blood samples from 180 PDAC patients and 573 healthy controls. Candidate markers consisted of 11 markers that are commonly expressed in various cancers and which have previously demonstrated increased expression in pancreatic cancer. Samples were divided into training and validation sets. Five linear or non-linear classification methods were used to determine the optimal model. Differences were identified in 10 out of the 11 markers tested. We identified 2047 combinations, all of which were applied to 5 separate algorithms. The new biomarker combination consisted of 6 markers (ApoA1, CA125, CA19-9, CEA, ApoA2, and TTR). The area under the curve, specificity, and sensitivity were 0.992, 95%, and 96%, respectively, in the training set. Meanwhile, the measures were 0.993, 96%, and 93% in the validation set. This study demonstrated the utility of multiple biomarker combinations in the early detection of PDAC. A diagnostic panel of 6 biomarkers was developed and validated. These algorithms will assist in the early diagnosis of PDAC.

Discovery of Novel Recurrent Mutations and Clinically Meaningful Subgroups in Nodal Marginal Zone Lymphoma.

Nodal marginal zone lymphoma (NMZL) is a rare B-cell neoplasm, the genetic and transcriptomic landscape of which are unclear. Using high-throughput sequencing for whole-exome and transcriptome, we investigated the genetic characteristics of NMZL in a discovery cohort (n = 8) and validated their features in an extended cohort (n = 30). Novel mutations in NFKBIE and ITPR2 were found in 7.9% (3/38) and 13.9% (5/36), respectively, suggesting roles for the NF-κB pathway and B-cell-receptor-mediated calcium signaling pathway in the pathogenesis of NMZL. RNA-seq showed that NMZLs were characterized by an aberrant marginal zone differentiation, associated with an altered IRF4-NOTCH2 axis and the enrichment of various oncogenic pathways. Based on gene expression profile, two subgroups were identified. Compared with subgroup 1, subgroup 2 showed the following: the significant enrichment of cell cycle-associated and MYC-signaling pathways, a more diverse repertoire of upstream regulators, and higher Ki-67 proliferation indices. We designated two subgroups according to Ki-67 labeling, and subgroup 2 was significantly associated with a shorter progression-free survival (p = 0.014), a greater proportion of large cells (p = 0.009), and higher MYC expression (p = 0.026). We suggest that NMZL has unique features and, in this study, we provide information as to the heterogeneity of this enigmatic entity.

Pentacyclic triterpenoid-rich fraction of the Hardy kiwi (Actinidia arguta) improves brain dysfunction in high fat diet-induced obese mice.

This study was performed to investigate the effect of the chloroform fraction from Actinidia arguta (CFAA) on cognitive dysfunction in a C57BL/6 mouse model fed a high-fat diet (HFD) for 12 weeks. The CFAA has the protective effect on high glucose-induced neurotoxicity in MC-IXC cell (neuroblastoma cell line). In a C57BL/6 mouse model fed a HFD for 12 weeks, the improved glucose tolerance and cognitive dysfunction were observed in a group ingesting CFAA. In the brain tissue analysis, the impaired cholinergic, antioxidant system and mitochondria functions were improved in the CFAA group. In addition, in a molecular biology study, it was observed that CFAA improves HFD-induced abnormal insulin signaling such as increase of IRS phosphorylation at serine residues and reduction of Akt phosphorylation caused by the increase of JNK phosphorylation and then inhibited apoptosis. In the UPLC Q-TOF/MS analysis, pentacyclic triterpenoids such as asiatic acid (AA), madecassic acid (MA) were identified in CFAA as main compounds. Therefore, these results propose that Actinidia arguta rich in pentacyclic triterpenoids may be effective as preventive matter a therapeutic strategy to improve neurodegenerative disease caused by HFD.

Clinicopathological features of programmed cell death-1 and programmed cell death-ligand-1 expression in the tumor cells and tumor microenvironment of angioimmunoblastic T cell lymphoma and peripheral T cell lymphoma not otherwise specified.

The expression patterns of programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) and their clinicopathological implications were investigated in peripheral T cell lymphoma (PTCL) including angioimmunoblastic T cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS). PTCL-NOS was further classified into nodal PTCL with follicular helper T cell (Tfh) phenotype ("PTCL-Tfh_new") and "PTCL-NOS_new". PD-1 and PD-L1 expression on tumor cells and reactive immune cells was evaluated using immunohistochemistry. PD-1 and PD-L1 expression on tumor cells (PD-1T and PD-L1T, respectively) was interpreted as positive when more than 5% of tumor cells expressed PD-1 or PD-L1. For PD-1 and PD-L1 on tumor cells and/or reactive immune cells (PD-1T + IC and PD-L1T + IC, respectively), a cutoff of 10% of cells was used. PD-1T, PD-L1T, and PD-L1T + IC expressions tended to be higher in AITLs than in PTCLs-NOS. PD-1T, PD-1T + IC, PD-L1T, and PD-L1T + IC expressions tended to be higher in PTCLs with Tfh phenotype including AITLs and "PTCL-Tfh_new" than in PTCLs without Tfh phenotype. The serum LDH level was significantly elevated in patients with PTCL positive for PD-L1T (P = 0.006) and PD-L1T + IC (P < 0.001). Patients with PTCL who were positive for combined expression of PD-1T/PD-L1T + IC presented at older ages (P = 0.010), nodal diseases (P = 0.001), higher IPI (P = 0.060), and elevated LDH (P = 0.030). Combined PD-1T/PD-L1T + IC positivity was related to shorter overall survival in patients with AITL (P = 0.051). Combined PD-1T/PD-L1T + IC positivity was a significant poor prognostic factor in patients with stage IV AITL, independent of B symptoms and performance status (HR = 6.282 [CI, 1.655-23.844], P = 0.007). In summary, the PD-1/PD-L1 pathway could be a potential prognostic and therapeutic biomarker for PTCL.

Identification of microRNAs modulated by DNA hypomethylating drugs in extranodal NK/T-cell lymphoma.

To identify epigenetically silenced miRNAs and to investigate their influences on predictive target oncogenes in extranodal natural killer/T-cell lymphoma (NKTCL). Decitabine treatment was performed to evaluate methylated miRNAs in NKTCL cells. The relationship between a given miRNA and its target mRNA was validated using 24 tumor tissues. miR-379, miR-134, miR-20b, miR-376a, miR-654-3p, miR-143, miR-181c, miR-1225-5p, miR-1246, and miR-1275 were epigenetically silenced in SNK6 cells. miR-134, miR-376a, miR-143 and miR-181c significantly affected cellular viability. PDGFRα was regulated by miR-34a and miR-181c. miR-143, miR-20b and miR34a regulated STAT3 expression. miR-20b and miR-143 expression showed inverse correlations with STAT3 mRNA expression in NKTCL tissues. K-RAS was regulated by miR-181c. Downregulation of cell viability by salirasib treatment was identified. miRNAs were downregulated by DNA methylation, and several microRNAs affected the viability of NKTCL cells. miR-34a and miR-181c may be involved in the oncogenic progression of NKTCL through the regulation of PDGFRα, STAT3, and K-RAS.