Circular RNA circPSAP functions as an efficient miR-331-3p sponge to regulate proliferation, apoptosis and bortezomib sensitivity of human multiple myeloma cells by upregulating HDAC4.

BACKGROUND: Multiple myeloma (MM) is a malignant tumor of plasma cells in the bone marrow. Circular RNAs (circRNAs) exert important activity in the tumorigenesis and chemoresistance of MM. In the current work, we sought to identify the expression, activity, and mechanism of circPSAP activity in MM. METHODS: CircPSAP, microRNA (miR)-331-3p, and histone deacetylase 4 (HDAC4) were quantified by qRT-PCR and immunoblotting assays. Cell proliferation and survival were assessed by CCK-8 assay. Cell cycle and apoptosis were detected by flow cytometry. The direct relationship between miR-331-3p and circPSAP or HDAC4 3'UTR was validated by dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays. RESULTS: CircPSAP was overexpressed in human MM and high levels of circPSAP predicted poor prognosis in MM patients. CircPSAP depletion repressed cell proliferation and promoted apoptosis and BTZ sensitivity. Mechanistically, circPSAP functioned as a miR-331-3p sponge, and circPSAP regulated cell proliferation, apoptosis and BTZ sensitivity by sponging miR-331-3p. MiR-331-3p directly targeted and inhibited HDAC4. MiR-331-3p-mediated inhibition of HDAC4 impaired cell proliferation and enhanced cell apoptosis and BTZ sensitivity. Moreover, circPSAP modulated HDAC4 expression by acting as a miR-331-3p sponge. CONCLUSION: Our findings highlight a novel mechanism, in which circPSAP functions as a miR-331-3p sponge to impact MM cell proliferation, apoptosis and BTZ sensitivity by regulating HDAC4 expression.

m6A methyltransferase Wilms' tumor 1-associated protein facilitates cell proliferation and cisplatin resistance in NK/T cell lymphoma by regulating dual-specificity phosphatases 6 expression via m6A RNA methylation.

Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor survival outcomes that is relatively resistant to chemotherapy. N6-Methyladenosine (m6A) modification, the most prevalent modification of eukaryotic messenger RNA, is involved in the progression of various tumors. However, it is unclear whether it has a physiological role in NKTCL development. To address this question, we probed its function and molecular mechanisms in NKTCL. Initially, we demonstrated that Wilms' tumor 1-associated protein (WTAP), a major RNA N6-adenosine methyltransferase, was obviously upregulated in human NKTCL cell lines (YTS and SNK-6 cells), compared with normal NK cells. Functionally, depletion of WTAP noticeably repressed proliferation and facilitated apoptosis in YTS and SNK-6 cells. Moreover, intervention of WTAP evidently prohibited NKTCL cell chemotherapy resistance to cisplatin, as reflected by a lower inhibition of cell viability and decreased expression of drug resistance-associated protein expression MRP-1 and P-gp in YTS and SNK-6 cells. With regard to the mechanism, we revealed that WTAP enhanced dual-specificity phosphatases 6 (DUSP6) expression by increasing m6A levels of DUSP6 mRNA transcript, leading to oncogenic functions in NKTCL. Interestingly, WTAP contributed to the progression and chemotherapy sensitivity of NKTCL by stabilizing DUSP6 mRNA in an m6A-dependent manner. Taken together, these findings uncovered a critical function for WTAP-guided m6A methylation and identified DUSP6 as an important target of m6A modification in the regulation of chemotherapy resistance in NKTCL oncogenesis. This study highlights WTAP as a potential therapeutic target of NKTCL treatment.

miR-1193 Suppresses the Proliferation and Invasion of Human T-Cell Leukemia Cells Through Directly Targeting the Transmembrane 9 Superfamily 3 (TM9SF3).

miRNAs have been involved in various types of cancer, including T-cell leukemia. In this study, the role of miR-1193 in the proliferation and invasion of T-cell leukemia cells was explored. First, we found that miR-1193 was sharply downregulated in T-cell leukemia cells when compared with normal T cells. miR-1193 markedly decreased the proliferation and invasion in Jurkat human T-cell leukemia cells. Transmembrane 9 superfamily 3 (TM9SF3) was then predicted to be a potential target gene of miR-1193, the levels of which displayed a strongly negative correlation with miR-1193 levels in T-cell leukemia patients. We confirmed that TM9SF3 was a target gene of miR-1193 by luciferase reporter gene assay. Finally, gene overexpression and knockdown experiments in Jurkat cells revealed that TM9SF3 positively regulated cell proliferation and invasion.

Effects of survivin on FVADT chemotherapy for refractory multiple myeloma.

The present study aimed to investigate the effects of survivin, an apoptosis inhibitor protein, on the efficacy of the fludarabine, vincristine, epirubicin, dexamethasone and thalidomide (FVADT) chemotherapy regime for the treatment of refractory multiple myeloma (MM). A total of 82 patients with MM were selected from the Hematology Inpatient Department at The Second Affiliated Hospital of Zhengzhou University (Zhengzhou, China). The initial treatment group consisted of 40 patients with MM, who received the vincristine, epirubicin and dexamethasone (VAD) chemotherapy regime. The refractory group consisted of 42 patients with refractory MM, who received the FVADT chemotherapy regime. Bone marrow biopsies were collected via marrow aspirations, and the protein expression of survivin was analyzed by immunohistochemistry. In addition, the Kaplan-Meier method was used for survival analyses. Intergroup differences in the protein expression levels of survivin were compared, and the association between survivin expression and the short- and long-term effects of FVADT chemotherapy were analyzed. The positive expression rate of survivin was significantly higher in the refractory group, as compared with the initial treatment group (P<0.05). Furthermore, the complete remission rate and the effective rate were significantly lower in the survivin-positive group, as compared with the survivin-negative group (P<0.05). The overall survival, progression free survival and 1 and 3 year survival rates of the survivin-positive group were significantly higher, as compared with the survivin-negative group (P<0.05). The results of the present study suggested that the protein expression of survivin was upregulated in refractory MM tissues, which was indicative of a poor short- and long-term efficacy for FVADT chemotherapy.

Differential protein analysis of lymphocytes between children with acute lymphoblastic leukemia and healthy children.

We identified differential proteins in lymphocytes between patients with childhood acute lymphoblastic leukemia (c-ALL) and healthy children. Samples of bone marrow lymphocytes from children with c-ALL and peripheral blood lymphocytes from healthy children were collected, and total proteins were extracted and separated from these samples followed by two-dimensional gel electrophoresis for comparative analysis. The differential protein spots in c-ALL cells were digested in situ, and then analyzed with matrix-assisted laser desorption ionization/time of flight mass spectrometry (MALDI-TOF-MS) followed by identification using the relevant database. Fifteen differential expression proteins were obtained by comparative proteomics analysis. Of the 15 differential proteins, eight were identified. Of the eight proteins, two had high expression and six low expression in c-ALL cells. The eight differential proteins are expected to become new diagnostic markers and drug targets for c-ALL.