A novel PPP2R2A::PRKD1 fusion in a cribriform adenocarcinoma of salivary gland.

Cribriform adenocarcinoma of salivary gland (CASG) is a rare, salivary gland tumor. In this report, we describe a case of CASG harboring a novel PPP2R2A::PRKD1 fusion. A 58-year-old female presented with an intraoral mass adjacent to the lower left third molar region. Morphological features at histological examination, immunohistochemical staining (p63+, p40-), and tumor location were indicative of CASG. However, due to the potential focal presence of a biphasic component within the tumor, RNA sequencing was performed to confirm the diagnosis. The subsequently found novel PPP2R2A::PRKD1 fusion adds to the rapidly evolving molecular landscape of salivary gland tumors. Additionally, we report that CASG may show some entrapment of pre-existent salivary gland ducts, which may be misinterpreted as tumor cells with myoepithelial differentiation.

microRNA-665 is down-regulated in gastric cancer and inhibits proliferation, invasion, and EMT by targeting PPP2R2A.

Recently, microRNA-665 (miR-665) has been reported to function as both tumour suppressor and oncogene in several cancer types, including gastric cancer, hepatocellular cancer, and lung cancer. However, the biological function of miR-665 and its precise mechanisms in gastric cancer (GC) have not been well clarified. The aim of this study was to study the roles of miR-665/PPP2R2A axis in GC. The levels of PPP2R2A and miR-665 were detected by quantitative PCR assay in GC tissues and cell lines. Moreover, the biological roles of miR-665 and PPP2R2A in GC cells were assessed by cell proliferation, invasion, and epithelial-mesenchymal transition (EMT). The mRNA and protein levels of PPP2R2A were determined by using quantitative PCR and Western blotting assays. Luciferase assays were used to confirm that PPP2R2A was one target of miR-665. In this study, the miR-665 level was dramatically reduced in GC tissues and cell lines, and the PPP2R2A expression was significantly enhanced. What is more, the PPP2R2A expression was negatively related to the miR-665 level in GC tissues. Furthermore, up-regulation of miR-665 obviously restrained GC cells proliferation, invasion, and EMT. We confirmed that miR-665 could directly target PPP2R2A by luciferase reporter assay. Besides, knockdown of PPP2R2A also could markedly inhibit the proliferation, invasion and EMT of GC cells. Finally, overexpression of miR-665 in GC cells partially reversed the promoted effects of PPP2R2A up-regulation. Overexpression of miR-665 restrained GC cells proliferation, invasion and EMT via regulation of PPP2R2A. SIGNIFICANCE OF THE STUDY: miR-665 has been reported to function as oncogene or tumour suppressor in different cancers. However, the precise roles of miR-665 in GC have not been elucidated. Our study for the first time demonstrated that miR-665 level was significantly down-regulated in GC. Additionally, miR-665 overexpression inhibited cell growth, invasion, and EMT of GC. Moreover, our data suggested a significant negative correlation between miR-665 and PPP2R2A expression in GC. MiR-665 suppressed GC cell proliferation, invasion, and EMT by directly targeting PPP2R2A, which suggested important roles for miR-665/PPP2R2A axis in the GC pathogenesis and its potential application in cancer therapy.

Differential Expression of Genes for Ubiquitin Ligases in Medulloblastoma Subtypes.

Using publically available datasets on gene expression in medulloblastoma (MB) subtypes, we selected genes for ubiquitin ligases and identified statistically those that best predicted each of the four major MB subgroups as separate disease entities. We identify a gene coding for an ubiquitin ligase, ZNRF3, whose overexpression alone can predict the WNT subgroup for 100% in the Pfister dataset. For the SHH subgroup, we identify a gene for a regulatory subunit of the protein phosphatase 2A (PP2A), PPP2R2C, as the major predictor among the E3 ligases genes. The ubiquitin and ubiquitin-like conjugation database (UUCD) lists PPP2R2C as coding for a Cullin Ring ubiquitin ligase adaptor. For group 3 MBs, the best ubiquitin ligase predictor was PPP2R2B, a gene which codes for another regulatory subunit of the PP2A holoenzyme. For group 4, the best E3 gene predictors were MID2, ZBTB18, and PPP2R2A, which codes for a third PP2A regulatory subunit. Heatmap analysis of the E3 gene data shows that expression of ten genes for ubiquitin ligases can be used to classify MBs into the four major consensus subgroups. This was illustrated by analysis of gene expression of ubiquitin ligases of the Pfister dataset and confirmed in the dataset of Cavalli. We conclude that genes for ubiquitin ligases can be used as genetic markers for MB subtypes and that the proteins coded for by these genes should be investigated as subtype specific therapeutic targets for MB.

PPP2R2A inhibition contributes to preeclampsia by regulating the proliferation, apoptosis, and angiogenesis modulation potential of mesenchymal stem cells.

BACKGROUND: The precise mechanisms underlying preeclampsia (PE) pathogenesis remain unclear. Mesenchymal stem cells (MSCs) are involved in the pathology of PE. The aim of our study was to identify the effects of protein phosphatase 2 regulatory subunit B α (PPP2R2A) on MSCs and ascertain its latent role in the progression of PE. METHODS: Reverse-transcription quantitative polymerase chain reaction and western blot analyses were performed to determine the expression of PPP2R2A in decidual tissue and decidual (d)MSCs from healthy pregnant women and patients with PE as well as the expression levels of Bax and Bcl-2 in dMSCs. The levels of p-PI3K, PI3K, p-AKT, and AKT were determined using western blotting. Cell growth, apoptosis, and migration were analyzed using MTT, flow cytometry, and Transwell assays, respectively. Human umbilical vein endothelial cell (HUVEC) tube formation ability was assayed using a HUVEC capillary-like tube formation assay. RESULTS: PPP2R2A was downregulated in decidual tissues and dMSCs of patients with PE when compared with that in healthy pregnant women. Moreover, upregulation of PPP2R2A enhanced cell proliferation, reduced apoptotic dMSC, inhibited Bax expression, and increased Bcl-2 levels. Conditioned medium from PPP2R2A-overexpressing dMSCs promoted HTR-8/SVneo cell migration and angiogenesis of HUVEC. Furthermore, the PPP2R2A plasmid suppressed PI3K/AKT pathway activation in dMSCs. However, these effects were partially reversed by LY2940002 treatment. CONCLUSION: PPP2R2A inhibition contributes to PE by regulating the proliferation, apoptosis, and angiogenesis of MSCs, providing a new therapeutic target for PE diagnosis and treatment.

PPP2R2A promotes Hu sheep pituitary cell proliferation and gonadotropin secretion associated with prolificacy.

The anterior pituitary plays a critical role in the endocrine system, contains gonadotrophs, which regulate reproductive efficiency by secreting follicle-stimulating hormone (FSH) and luteinizing hormone (LH). PPP2R2A is a serine-threonine phosphatase that regulates reproductive functions in both females and males, its function in pituitary cells remain unclear. Hu sheep is a highly prolific breed, which makes it suitable for studying reproductive mechanisms. In this study, the relative abundances of PPP2R2A mRNA expression were higher in the pituitary of high-prolificacy (HF) Hu sheep compared to those of low-prolificacy (LF) Hu sheep. Additionally, we demonstrated that PPP2R2A promotes pituitary cell proliferation and gonadotropin secretion using the EdU assay and ELISA, respectively. Moreover, it inhibits pituitary cell apoptosis using flow cytometry. Furthermore, PPP2R2A may affect pituitary cell function by regulating the AKT/mTOR signaling pathway. In summary, our findings suggest that PPP2R2A may play a role in regulating pituitary function and influencing the secretion of gonadotropins.

The PP2A regulatory subunit PPP2R2A controls NAD+ biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.

The protein phosphatase 2A (PP2A) regulatory subunit PPP2R2A is involved in the regulation of immune response. We report that lupus-prone mice with T cells deficient in PPP2R2A display less autoimmunity and nephritis. PPP2R2A deficiency promotes NAD+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. NR inhibits murine Th17 and promotes Treg cell differentiation, in vitro, by PΑRylating histone H1.2 and causing its reduced occupancy in the Foxp3 loci and increased occupancy in the Il17a loci, leading to increased Foxp3 and decreased Il17a transcription. NR treatment suppresses disease in MRL.lpr mice and restores NAD+-dependent poly [ADP-ribose] polymerase 1 (PARP1) activity in CD4 T cells from patients with systemic lupus erythematosus (SLE), while reducing interferon (IFN)-γ and interleukin (IL)-17 production. We conclude that PPP2R2A controls the level of NAD+ through the NR-directed salvage pathway and promotes systemic autoimmunity. Translationally, NR suppresses lupus nephritis in mice and limits the production of proinflammatory cytokines by SLE T cells.

PP2A-B55 phosphatase counteracts Ki-67-dependent chromosome individualization during mitosis.

Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.

The role of miR-222-2p in exosomes secreted by hexavalent chromium-induced premature senescent hepatocytes as a SASP component.

With the development of world industrialization, the environmental pollution of hexavalent chromium [Cr(VI)] is becoming an increasingly serious problem. In particular, the mechanisms by which long-term and low-dose exposure to Cr(VI) leading the development of related cancers are not well understood. As senescent cells gradually lose their ability to proliferate and divide, they will not be malignantly transformed. However, Senescence-associated secretory phenotype (SASP) released by senescent cells into the cellular microenvironment can act on neighboring cells. Since SASP has a bidirectional regulatory role in the malignant transformation of cells. Hence, It is very necessary to identified the composition and function of SASP which secreted by Cr(VI) induced senescent L02 hepatocytes (S-L02). Exosomes, a vesicle-like substances released extracellularly after the fusion of intracellular multivesicular bodies with cell membrane, are important components of SASP and contain a large number of microRNAs (miRNAs). By establishing Cr(VI)-induced S-L02 model, we collected the exosomes from the supernatants of S-L02 and L02 culture medium respectively, and screened out the highly expressed miRNAs in the exosomes of S-L02, namely the new SASP components. Among them, the increase of miR-222-5p was the most significant. It was validated that as SASP, miR-222-5p can inhibit the proliferation of L02 and S-L02 hepatocytes and at the same time accelerate the proliferation and migration ability of HCC cells. Further mechanistic studies revealed that miR-222-5p attenuated the regulatory effect of protein phosphatase 2A subunit B isoform R2-α (PPP2R2A) on Akt via repressing its target gene PPP2R2A, causing reduced expressions of forkhead box O3 (FOXO3a), p27 and p21, and finally increasing the proliferation of HCC cells after diminishing the negative regulation of on cell cycle. This study certainly provides valuable laboratory evidence as well as potential therapeutic targets for the prevention and further personalized treatment of Cr(VI)-associated cancers.

Genetic Rearrangements in Different Salivary Gland Tumors: A Systematic Review.

Salivary gland tumors (SGT) encompass a wide range of neoplasms, each with its own unique histological type and clinical presentation. This review hones in on prevalent subtypes of SGTs, including adenoid cystic carcinoma (ACC), salivary duct carcinoma (SDC), and polymorphous adenocarcinoma (PAC). The articles, identified through specific keywords, were meticulously screened in databases like PubMed, Scopus, Google Scholar, and Web of Science from 2018 to 2023. Eight articles delved into genetic modifications among the selected SGT types. A fusion protein known as MYB-NF1B is typically associated with ACC, promoting cell proliferation while inhibiting apoptosis. The presence of MYB modifications in ACCs is a beacon of hope, as it is linked to a more favorable prognosis. In contrast, SDCs often exhibit HER2 expression. The invasive nature of SGTs contributes to their resistance to treatment. In the case of PAC, the role of PRKD1 is particularly noteworthy. PRKD1, integrated with other genes from the PRKD1/2/3 cluster, helps to differentiate PAC from other diseases. Furthermore, the genetic profiles of KTN1-PRKD1) and PPP2R2A:PRKD1 are distinct. The significant genetic variability among SGTs necessitates meticulous examination. This field is in a constant state of evolution, with new discoveries reshaping our understanding. Genetics is a key player in deciphering SGTs and tailoring treatments. This complex neoplasm demands ongoing research to uncover all genetic influences, thereby enhancing diagnostic methodologies, therapeutic strategies, and patient outcomes.

PPP2R2A promotes testosterone secretion in Hu sheep Leydig cells via activation of the AKT/mTOR signaling pathway.

The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme complex that plays a vital role in regulating male reproductive activities. However, as an essential member of the PP2A family, the physiological functions of PP2A regulatory subunit B55α (PPP2R2A) in testis remain inconclusive. Hu sheep are noted for their reproductive precocity and fertility, and are ideal models for the study of male reproductive physiology. Here, we analyzed the expression patterns of PPP2R2A in the male Hu sheep reproductive tract at different developmental stages and further investigated its role in testosterone secretion and its underlying mechanisms. In this study, we found that there were temporal and spatial differences in PPP2R2A protein expression in the testis and epididymis, especially the expression abundance in the testis at 8 months old (8M) was higher than that at 3 months old (3M). Interestingly, we observed that PPP2R2A interference reduced the testosterone levels in the cell culture medium, which is accompanied by a reduction in Leydig cell proliferation and an elevation in Leydig cell apoptosis. The level of reactive oxygen species in cells increased significantly, while the mitochondrial membrane potential (ΔΨm) decreased significantly after PPP2R2A deletion. Meanwhile, the mitochondrial mitotic protein DNM1L was significantly upregulated, while the mitochondrial fusion proteins MFN1/2 and OPA1 were significantly downregulated after PPP2R2A interference. Furthermore, PPP2R2A interference suppressed the AKT/mTOR signaling pathway. Taken together, our data indicated that PPP2R2A enhanced testosterone secretion, promoted cell proliferation, and inhibited cell apoptosis in vitro, all of which were associated with the AKT/mTOR signaling pathway.

AMOTL2 inhibits JUN Thr239 dephosphorylation by binding PPP2R2A to suppress the proliferation in non-small cell lung cancer cells.

Protein phosphatase 2A (PP2A) complex comprises an extended family of intracellular protein serine/threonine phosphatases, that participate in different signaling transduction pathways. Different functions of PP2As are determined by the variety of regulatory subunits. In this study, CRISPR/Cas9-mediated loss-of-function screen revealed that PPP2R2A downregulation suppressed cell growth in NSCLC cells. AMOTL2 was identified and confirmed as a novel binding partner of PPP2R2A in NSCLC cells by mass spectrometry, CO-IP, GST pull-down and immunofluorescence. Upregulation of AMOTL2 also led to cell proliferation delay in human and mouse lung tumor cells. The proto-oncogene JUN is a key subunit of activator protein-1 (AP-1) transcription factor which plays crucial role in regulating tumorigenesis and its activity is negatively regulated by the phosphorylation at T239. Our results showed that either AMOTL2 upregulation or PPP2R2A downregulation led to great increase in JUN T239 phosphorylation. AMOTL2 bound PPP2R2A in cytoplasm, which reduced nuclear localization of PPP2R2A. In conclusion, AMOTL2 and PPP2R2A act respectively as negative and positive regulator of cell growth in NSCLC cells and function in the AMOTL2-PPP2R2A-JUN axis, in which AMOTL2 inhibits the entry of PPP2R2A into the nucleus to dephosphorylate JUN at T239.

PPP2R2A affects embryonic implantation by regulating the proliferation and apoptosis of Hu sheep endometrial stromal cells.

Embryonic implantation is a complex reproductive physiological process in mammals. Although several endometrial proteins affecting embryonic implantation have been reported in the past, there are still potential endometrial proteins that have been neglected, and their specific regulatory mechanisms are unclear. This study demonstrated that protein phosphatase 2A regulatory subunit B55α (PPP2R2A) served as a novel regulator in medication of sheep embryonic implantation in vitro. Our results showed that sheep PPP2R2A encoded 447 amino acids and shared 91.74%-92.36% amino acid sequences with its orthologs compared with other species. Meanwhile, PPP2R2A was widely expressed in sheep uterine tissues, and it could regulate the expression levels of key regulators of embryonic implantation in endometrial stromal cells (ESCs). Knockdown of PPP2R2A significantly inhibited cell proliferation by blocking cell cycle transfer G0/G1 into S phase accompanied by downregulation of CDK2, CDK4, CCND1, CCNE1 and upregulation of P21. In contrast to PPP2R2A overexpression, PPP2R2A interference greatly promoted cell apoptosis and the expression of BAX, CASP3, CASP9 and BAX/BCL-2. Taken together, these results suggest that PPP2R2A, as a novel regulatory factor, affects embryonic implantation via regulating the proliferation and apoptosis of Hu sheep ESCs in vitro.

Analysis of CRISPR-Cas9 screens identifies genetic dependencies in melanoma.

Targeting the MAPK signaling pathway has transformed the treatment of metastatic melanoma. CRISPR-Cas9 genetic screens provide a genome-wide approach to uncover novel genetic dependencies that might serve as therapeutic targets. Here, we analyzed recently reported CRISPR-Cas9 screens comparing data from 28 melanoma cell lines and 313 cell lines of other tumor types in order to identify fitness genes related to melanoma. We found an average of 1,494 fitness genes in each melanoma cell line. We identified 33 genes, inactivation of which specifically reduced the fitness of melanoma. This set of tumor type-specific genes includes established melanoma fitness genes as well as many genes that have not previously been associated with melanoma growth. Several genes encode proteins that can be targeted using available inhibitors. We verified that genetic inactivation of DUSP4 and PPP2R2A reduces the proliferation of melanoma cells. DUSP4 encodes an inhibitor of ERK, suggesting that further activation of MAPK signaling activity through its loss is selectively deleterious to melanoma cells. Collectively, these data present a resource of genetic dependencies in melanoma that may be explored as potential therapeutic targets.

Circ_0137287 suppresses cell tumroigenesis and aerobic glycolysis in papillary thyroid carcinoma through miR-183-5p/PPP2R2A axis.

Circ_0137287 was found to be decreased in papillary thyroid cancer (PTC) tissues and related to aggressive clinicopathologic characteristics. However, the role and mechanism of circ_0137287 in PTC remain vague. Circ_0137287 expression was decreased in PTC and its low expression predicted poor survival. The ROC analysis suggested circ_0137287 might be a marker for PTC diagnosis. Circ_0137287 overexpression in PTC cells impaired cell proliferation, migration, invasion, and aerobic glycolysis, but induced apoptosis in vitro and in vivo. Circ_0137287 specifically bound to miR-183-5p, and miR-183-5p reversed the inhibitory effects of circ_0137287 on PTC tumor growth, motility and aerobic glycolysis. MiR-183-5p directly targeted PPP2R2A, and promoted PTC progression through regulating PPP2R2A. Mechanistically, circ_0137287 could indirectly modulate PPP2R2A expression through targeting miR-183-5p. Circ_0137287 suppressed PTC tumorigenesis and aerobic glycolysis through up-regulating PPP2R2A via miR-183-5p absorption, indicating a promising prognostic, diagnostic and therapeutic target.

LncRNA-HCG18 regulates the viability, apoptosis, migration, invasion and epithelial-mesenchymal transition of papillary thyroid cancer cells via regulating the miR-106a-5p/PPP2R2A axis.

The incidence of papillary thyroid cancer (PTC) has experienced a rapid increase in recent years. Long non-coding RNA-homo sapiens HLA complex group (HCG) 18 plays a regulatory role in cancers, but its role in PTC remained unknown. This study determined the expressions of HCG18, microRNA (miR)-106a-5p, and protein phosphatase 2 regulatory subunit B alpha (PPP2R2A) in PTC tissues and cells by qRT-PCR. ENCORI predicted the targeting relation between HCG18 and miR-106a-5p. TargetScan v7.2 predicted the targeting relation between miR-106a-5p and PPP2R2A. Dual-luciferase reporter assay was performed to validate the two targeting relations. The viability, migration, and invasion of PTC cells were detected by Cell Counting Kit-8, wound healing assay, and Transwell assay, respectively. The expressions of matrix metalloproteinase 2 (MMP-2), MMP-9, E-cadherin, N-cadherin, and Vimentin in TPC-1 and MDA-T68 cells were assessed by qRT-PCR and Western blot. It was found that HCG18 was down-regulated in PTC. Overexpressing HCG18 suppressed viability, migration, and invasion, promoted apoptosis, and inhibited miR-106a-5p expression in PTC cells. HCG18 interacted with miR-106a-5p, the expression of which was upregulated in PTC. Upregulating miR-106a-5p expression by lentivirus infection promoted viability, migration and invasion and inhibited apoptosis of PTC cells, reversed the effect of HCG18 on the biological behaviors of PTC cells, and promoted the expressions of MMP-2, MMP-9, E-cadherin, and Vimentin and downregulated E-cadherin expression in PTC cells. PPP2R2A, a direct target of miR-106a-5p, was downregulated in PTC, and HCG18 promoted PPP2R2A expression in PTC cells by sponging miR-106a-5p. Furthermore, PPP2R2A reversed the effects of miR-106a-5p on PTC cells. In conclusion, HCG18 suppressed viability, migration, invasion and epithelial-mesenchymal transition and promoted apoptosis of PTC cells via regulating the miR-106a-5p/PPP2R2A axis.

Hepsin Promotes Epithelial-Mesenchymal Transition and Cell Invasion Through the miR-222/PPP2R2A/AKT Axis in Prostate Cancer.

PURPOSE: To determine the role and underlying mechanism of hepsin in epithelial-mesenchymal transition (EMT) and cell invasion in prostate cancer. METHODS: The expression of hepsin in prostate cancer tissue samples and cell lines was measured by immunohistochemical staining and Western blotting. The EMT and cell invasion abilities of prostate cancer cells were detected by Western blot and transwell assays. RNA transfection was used to inhibit or overexpress related genes. The expression of miR-222 was detected by RT-qPCR. A dual­luciferase reporter gene assay was performed to determine the target of miR-222. RESULTS: Hepsin expression was upregulated in prostate cancer tissue samples and cell lines. Inhibition of hepsin attenuated EMT and cell invasion and downregulated the expression of miR-222. Decreased miR-222 expression enhanced the level of PPP2R2A, which in turn attenuated the AKT signaling. Activation of miR-222 or AKT could block the inhibitory effects on EMT and cell invasion induced by hepsin deficiency. CONCLUSION: Hepsin promotes EMT and cell invasion through the miR-222/PPP2R2A/AKT axis in prostate cancer.

Hsa-MiR-590-3p Promotes the Malignancy Progression of Pancreatic Ductal Carcinoma by Inhibiting the Expression of p27 and PPP2R2A via G1/S Cell Cycle Pathway.

OBJECTIVE: To investigate the effect of miR-590-3p on the malignant biological behavior of pancreatic cancer, and to explore the target genes and pathways directly affected by miR-590-3p, to provide new therapeutic ideas and targets for the study of the diagnosis and treatment of pancreatic cancer. METHODS: We used qRT-PCR to measure miR-590-3p expression quantities. We used cell cycle, CCK-8, clonal formation to verify the change of proliferation capacity of PC cells. We used transwell assay to detect the migration and invasion of PC cells. We used the bioinformatics tool TargetScan (http://www.targetscan.org) to identify the possible target genes of miR-590-3p. Immunohistochemistry revealed the clinicopathological significance of PPP2R2A, p27 and miR-590-3p in the expression of pancreatic cancer. Western blot was used to detect the expression changes of PPP2R2A, p27 and G1/S cell cycle pathway-related proteins CDK2, cyclinE2 and p21 after transfection of mimics and inhibitors of miR-590-3p. RESULTS: According to our study, hsa-miR-590-3p expression was significantly higher in PC tissues than that in paired normal pancreas, which was associated with PC tumor size (P=0.042) and preoperative CA19-9 level (P=0.046) of PC patients. Its overexpression promoted PC cell proliferation, invasion and migration following with the p27 and PPP2R2A protein downregulation in Capan-2, PANC-1 and BxPC-3 cells, and vice versa. Bioinformatics analysis and dual-luciferase reporter assay further confirmed that p27 and PPP2R2A were direct target genes of miR-590-3p. The negative relationship of miR-590-3p with p27 and PPP2R2A was also observed in PC tissues. CONCLUSION: MiR-590-3p promotes the proliferation, migration and invasion of pancreatic cancer cells. MiR-590-3p directly downregulated p27 and PPP2R2A and via the G1/S cell cycle pathway to promote the development of pancreatic cancer.

MicroRNA-221 promotes cisplatin resistance in osteosarcoma cells by targeting PPP2R2A.

Osteosarcoma (OS), the most common malignant bone tumor, is the main cause of cancer-related deaths in children and young adults. Despite the combination of surgery and multi-agent chemotherapy, patients with OS who develop resistance to chemotherapy or experience recurrence have a dismal prognosis. MicroRNAs (miRNAs) are a class of small noncoding RNAs that repress their targets by binding to the 3'-UTR and/or coding sequences, leading to the inhibition of gene expression. miR-221 is found to be up-regulated in tumors when compared with their matched normal osteoblast tissues. We also observed significant miR-221 up-regulation in the OS cell lines, MG-63, SaoS-2, and U2OS, when compared with the normal osteoblast cell line, HOb. Overexpression of miR-221 promoted OS cell invasion, migration, proliferation, and cisplatin resistance. MG-63 and SaoS-2 cells transfected with miR-221 mimics were more resistant to cisplatin. The IC50 of MG-63 cells transfected with control mimics was 1.24 µM. However, the IC50 of MG-63 cells overexpressing miR-221 increased to 7.65 µM. Similar results were found in SaoS-2 cells, where the IC50 for cisplatin increased from 3.65 to 8.73 µM. Thus, we report that miR-221 directly targets PP2A subunit B (PPP2R2A) in OS by binding to the 3'-UTR of the PPP2R2A mRNA. Restoration of PPP2R2A in miR-221-overexpressing OS cells recovers the cisplatin sensitivity of OS cells. Therefore, the present study suggests a new therapeutic approach by inhibiting miR-221 for anti-chemoresistance in OS.

Overexpression of miR-222-3p Promotes the Proliferation and Inhibits the Apoptosis of Diffuse Large B-Cell Lymphoma Cells via Suppressing PPP2R2A.

PURPOSE: This study aimed to investigate the effects of microRNA-222-3p on activated B cell-like-type diffuse large B-cell lymphoma cells and the regulatory relationship between microRNA-222-3p and phosphatase 2 regulatory subunit B alpha. METHOD: The expression of microRNA-222-3p was detected in activated B cell-like-type diffuse large B-cell lymphoma tissues and cells by quantitative reverse transcription polymerase chain reaction. The regulatory effects of microRNA-222-3p on the proliferation, invasion, and apoptosis of activated B cell-like-type diffuse large B-cell lymphoma cells were analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, flow cytometry, and Transwell assay. The regulatory relationship between microRNA-222-3p and phosphatase 2 regulatory subunit B alpha was determined by luciferase reporter gene and RNA pull-down assay. In addition, the effects of microRNA-222-3p on tumor growth were further analyzed in mice. RESULTS: MicroRNA-222-3p and phosphatase 2 regulatory subunit B alpha were significantly up- and downregulated in activated B cell-like-type diffuse large B-cell lymphoma tissues and cells, respectively. Phosphatase 2 regulatory subunit B alpha was a target of microRNA-222-3p. MicroRNA-222-3p promoted the proliferation and invasion and inhibited the apoptosis of activated B cell-like-type diffuse large B-cell lymphoma cells. Phosphatase 2 regulatory subunit B alpha reversed the tumor-promoting effects of microRNA-222-3p on activated B cell-like-type diffuse large B-cell lymphoma cells. In addition, microRNA-222-3p promoted the tumor growth in mice and downregulated phosphatase 2 regulatory subunit B alpha in tumor tissues. CONCLUSION: MicroRNA-222-3p promoted the proliferation and invasion and inhibited the apoptosis of activated B cell-like-type diffuse large B-cell lymphoma cells through suppressing phosphatase 2 regulatory subunit B alpha expression.

PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer.

PP2A is a highly conserved eukaryotic serine/threonine protein phosphatase of the PPP family of phosphatases with fundamental cellular functions. In cells, PP2A targets specific subcellular locations and substrates by forming heterotrimeric holoenzymes, where a core dimer consisting of scaffold (A) and catalytic (C) subunits complexes with one of many B regulatory subunits. PP2A plays a key role in positively and negatively regulating a myriad of cellular processes, as it targets a very sizable fraction of the cellular substrates phosphorylated on Ser/Thr residues. This review focuses on insights made toward the understanding on how the subunit composition and structure of PP2A holoenzymes mediates substrate specificity, the role of substrate modulation in the signaling of cellular division, growth, and differentiation, and its deregulation in cancer.