LncRNA EBLN3P Accelerates Cell Proliferation and Invasion of Colon Cancer through Modulating the miR-519d-3p/ZFP91 Axis.

Purpose: The study aims to explore the roles and underlying mechanisms of long noncoding RNAs endogenous bornavirus-like nucleoprotein (lncRNA EBLN3P) in colon cancer, emphasizing the potential impact of these insights on advancing colon cancer treatment strategies. By shedding light on lncRNA EBLN3P's involvement, this research could contribute to the development of novel therapeutic approaches, enhancing the efficacy of interventions for colon cancer patients. Methods: We employed quantitative reverse transcription polymerase chain reaction to assess the levels of lncRNA EBLN3P, zinc finger protein (ZFP91), and miR-519d-3p, alongside CCK-8 and EdU assays for cell proliferation, flow cytometry for apoptosis, and Transwell and wound healing assays for migration and invasion. The in vivo function of lncRNA EBLN3P was investigated through a xenograft model, and protein levels were evaluated via Western blot analysis. Results: LncRNA EBLN3P was found to be upregulated in colon cancer tissues and cells, promoting cell proliferation and metastasis while inhibiting apoptosis. Downregulation of lncRNA EBLN3P reduced tumor size, volume, and weight in a mouse model. MiR-519d-3p, which negatively interacts with lncRNA EBLN3P, was found to be downregulated in colon cancer tissues and cell lines. Its upregulation hindered cancer cell proliferation and metastasis while enhancing apoptosis. ZFP91, a binding partner of miR-519d-3p, was upregulated in colon cancer and inversely related to miR-519d-3p levels. Rescue experiments indicated that the effects of lncRNA EBLN3P silencing could be reversed by miR-519d-3p suppression, but were mitigated by ZFP91 downregulation. Conclusion: LncRNA EBLN3P facilitates colon cancer progression via the miR-519d-3p/ZFP91 axis, presenting a novel understanding of lncRNA EBLN3P's role and offering potential therapeutic insights for colon cancer treatment. This study fills a critical gap by linking lncRNA EBLN3P with the miR-519d-3p/ZFP91 axis in the context of colon cancer, thereby broadening our understanding of the molecular mechanisms underlying colon cancer progression.

MALAT1 promotes FOXA1 degradation by competitively binding to miR-216a-5p and enhancing neuroendocrine differentiation in prostate cancer.

OBJECTIVES: Prostate cancer (PC) is a leading cause of cancer-related death in males worldwide. Neuroendocrine differentiation (NED) is a feature of PC that often goes undetected and is associated with poor patient outcomes. Long non-coding RNAs (lncRNAs), microRNAs (miRNAs/miRs), and messenger RNAs (mRNAs) play important roles in the development and progression of PC. METHODS: In this study, we used transcriptome sequencing and bioinformatics analysis to identify key regulators of NED in PC. Specifically, we examined the expression of PC-related lncRNAs, miRNAs, and mRNAs in PC cells and correlated these findings with NED phenotypes. RESULTS: Our data revealed that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and zinc finger protein 91 (ZFP91) were upregulated in PC, while miR-216a-5p was down-regulated. Ectopic expression of MALAT1 induced NED and promoted malignant phenotypes of PC cells. Furthermore, we found that MALAT1 competitively bound to miR-216a-5p, upregulated ZFP91, and promoted the degradation of forkhead box A1 (FOXA1), a key gene involved in NED of PC. CONCLUSION: Taken together, these results suggest that MALAT1 plays an oncogenic role in NED and metastasis of PC via the miR-216a-5p/ZFP91/FOXA1 pathway. Our study highlights the potential of targeting this pathway as a novel therapeutic strategy for PC.

Atypical E3 ligase ZFP91 promotes small-molecule-induced E2F2 transcription factor degradation for cancer therapy.

BACKGROUND: The E2F family of transcription factors play a crucial role in the development of various cancers. However, E2F members lack targetable binding pockets and are typically considered "undruggable". Unlike canonical small-molecule therapeutics, molecular glues mediate new E3 ligase-protein interactions to induce selective proteasomal degradation, which represents an attractive option to overcome these limitations. METHODS: Human proteome microarray was utilized to identify a natural product-derived molecular glue for targeting E2F2 degradation. Co-IP analysis with stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics was carried out to further explore the E3 ligase for E2F2 degradation. FINDINGS: In this study, we identified a molecular glue bufalin, which significantly promoted E2F2 degradation. Unexpectedly, E2F2 underwent ubiquitination and proteasomal degradation via a previously undisclosed atypical E3 ligase, zinc finger protein 91 (ZFP91). In particular, we observed that bufalin markedly promoted E2F2-ZFP91 complex formation, thereby leading to E2F2 polyubiquitination via K48-linked ubiquitin chains for degradation. E2F2 degradation subsequently caused transcriptional suppression of multiple oncogenes including c-Myc, CCNE1, CCNE2, MCM5 and CDK1, and inhibited hepatocellular carcinoma growth in vitro and in vivo. INTERPRETATION: Collectively, our findings open up a new direction for transcription factors degradation by targeting atypical E3 ligase ZFP91. Meanwhile, the chemical knockdown strategy with molecular glue may promote innovative transcription factor degrader development in cancer therapy. FUNDING: This work was financially supported by the National Key Research and Development Project of China (2022YFC3501601), National Natural Sciences Foundation of China (81973505, 82174008, 82030114), and China Postdoctoral Science Foundation (2019M650396), the Fundamental Research Funds for the Central Universities.

Ginsenoside Rg3 increases gemcitabine sensitivity of pancreatic adenocarcinoma via reducing ZFP91 mediated TSPYL2 destabilization.

Background: Ginsenoside Rg3 and gemcitabine have mutual enhancing antitumor effects. However, the underlying mechanisms are not clear. This study explored the influence of ginsenoside Rg3 on Zinc finger protein 91 homolog (ZFP91) expression in pancreatic adenocarcinoma (PAAD) and their regulatory mechanisms on gemcitabine sensitivity. Methods: RNA-seq and survival data from The Cancer Genome Atlas (TCGA)-PAAD and Genotype-Tissue Expression (GTEx) were used for in-silicon analysis. PANC-1, BxPC-3, and PANC-1 gemcitabine-resistant (PANC-1/GR) cells were used for in vitro analysis. PANC-1 derived tumor xenograft nude mice model was used to assess the influence of ginsenoside Rg3 and ZFP91 on tumor growth in vivo. Results: Ginsenoside Rg3 reduced ZFP91 expression in PAAD cells in a dose-dependent manner. ZFP91 upregulation was associated with significantly shorter survival of patients with PAAD. ZFP91 overexpression induced gemcitabine resistance, which was partly conquered by ginsenoside Rg3 treatment. ZFP91 depletion sensitized PANC-1/GR cells to gemcitabine treatment. ZFP91 interacted with Testis-Specific Y-Encoded-Like Protein 2 (TSPYL2), induced its poly-ubiquitination, and promoted proteasomal degradation. Ginsenoside Rg3 treatment weakened ZFP91-induced TSPYL2 poly-ubiquitination and degradation. Enforced TSPYL2 expression increased gemcitabine sensitivity of PAAD cells and partly reversed induced gemcitabine resistance in PANC-1/GR cells. Conclusion: Ginsenoside Rg3 can increase gemcitabine sensitivity of pancreatic adenocarcinoma at least via reducing ZFP91 mediated TSPYL2 destabilization.

Silencing LINC00491 Inhibits Pancreatic Cancer Progression through MiR-188-5p-induced Inhibition of ZFP91.

Background: Pancreatic cancer is recognized as one of the most malignant tumors with poor prognosis. Recently, long noncoding RNAs (lncRNAs) are considered as a potential prognostic biomarker of PC. However, the concrete biological effect of lncRNAs in PC remains unmasked. Herein, we explored the mechanism of LINC00491 in PC. Methods: Quantitative real-time PCR (qRT-PCR) was administrated to detected the expression of LINC00491 in PC tissues and cell lines. Loss-of-function experiment in vitro and in vivo was carried out to figure out the biological effects of LINC00491 on PC carcinogenesis. Luciferase reporter assay, subcellular fractionation, western blotting, pull-down assay and RNA immunoprecipitation assay were further used to explore the mechanism of PC tumorigenesis of LINC00491. Results: An increase of LINC00491 was detected in PC cell lines and tissues. Silencing LINC00491 in vitro and in vivo subsequently hindered cell migration, invasion, proliferation and tumor growth, respectively. Further research confirmed a negative and a positive connection of LINC00491 with microRNA 188-5p (miR-188-5p) level and Zinc finger protein 91 (ZFP91), a target of miR-188-5p, respectively. qRT-PCR and western blotting found that miR-188-5p was upregulated while LINC00491 was downregulated, concomitant with ZFP91 decreasing in PC cells or node mouse tumors, which could be significantly restored by inhibiting miR-188-5p. Besides, overexpression of miR-188-5p partially restored the inhibitory effect of LINC00491 diminution on proliferation, migration, and invasion of PC cells. Conclusion: LINC00491 promotes PC proliferation, migration, invasion via the miR-188-5p/ZFP91 axis, suggesting LINC00491 could be a new therapeutic target for PC.

ZFP91 promotes cell proliferation and inhibits cell apoptosis in AML via inhibiting the proteasome-dependent degradation of RIP1.

Acute myeloid leukemia (AML) is a quickly progressive and devastated hematological malignancy with large rate of relapse and the appearance of chemotherapy resistance. Therefore, the identification of new therapeutic targets is urgent. ZFP91 is a hidden oncogene. Nevertheless, how ZFP91 takes part in regulating AML is less clear. Our research aims at investigating the molecular mechanisms and uncovering the effects of ZFP91 on AML. This research demonstrates that ZFP91 boosts AML cell proliferation and stops AML cell apoptosis. Mechanistically, experimental results showed the interaction between ZFP91 and RIP1 and inhibitory effect of ZFP91 on the K48-linked ubiquitination of endogenous RIP1, which is an important molecule in AML. Taken together, our results provide the evidence that targeted inhibition of ZFP91 could be a hopeful measure to treat AML.

Convallatoxin inhibits IL-1ß production by suppressing zinc finger protein 91 (ZFP91)-mediated pro-IL-1ß ubiquitination and caspase-8 inflammasome activity.

BACKGROUND AND PURPOSE: ZFP91 positively regulates IL-1ß production in macrophages and may be a potential therapeutic target to treat inflammatory-related diseases. We investigated whether this process is modulated by convallatoxin, which is a cardiac glycoside isolated from the traditional Chinese medicinal plant Adonis amurensis Regel et Radde. EXPERIMENTAL APPROACH: In vitro, the mechanisms by which convallatoxin inhibits ZFP91-regulated IL-1ß expression were investigated using molecular docking, western blotting, RT-PCR, ELISA, immunofluorescence and immunoprecipitation assays.In vivo, mice liver injury was induced by an intraperitoneal injection of D-GalN and LPS, colitis was induced by oral administration of dextran sulfate sodium (DSS) in drinking water and peritonitis was induced by an intraperitoneal injection of alum. KEY RESULTS: We confirmed that convallatoxin inhibited the release of IL-1ß by down-regulating ZFP91. Importantly, we found that convallatoxin significantly reduced K63-linked polyubiquitination of pro-IL-1ß regulated by ZFP91 and decreased the efficacy of pro-IL-1ß cleavage. Moreover, convallatoxin suppressed ZFP91-mediated activation of the non-canonical cysteine-requiring aspartate protease-8 (caspase-8) inflammasome and MAPK signalling pathways in macrophages. Furthermore, we showed that ZFP91 promoted the assembly of the caspase-8 inflammasome complex, whereas convallatoxin treatment reversed this result. Mice in vivo studies further demonstrated that convallatoxin ameliorated D-GalN/LPS-induced liver injury, DSS-induced colitis and alum-induced peritonitis by down-regulating ZFP91. CONCLUSION AND IMPLICATIONS: We show for the first time that convallatoxin-mediated inhibition of ZFP91 is an important regulatory event that prevents inappropriate inflammatory responses to maintain immune homeostasis. This mechanism provides new insight for the development of convallatoxin as a novel anti-inflammatory drug targeting ZFP91. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

Panaxadiol inhibits IL-1ß secretion by suppressing zinc finger protein 91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of Panax ginseng C.A.Mey. in traditional Chinese medicine dates back to about 5000 years ago thanks to its several beneficial and healing properties. Panaxadiol is a triterpenoid sapogenin monomer found in the roots of Panax ginseng C.A.Mey. and has been proven to have various bio-activities such as anti-inflammatory, anti-tumour and neuroprotective effects. AIM OF THE STUDY: The present study focuses on investigating the inflammation inhibitory effect and mechanism of panaxadiol by regulating zinc finger protein 91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages. MATERIALS AND METHODS: In vitro, the underlying mechanisms by which panaxadiol inhibits ZFP91-regulated IL-1ß expression were investigated using molecular docking, western blotting, RT-PCR, ELISA, immunofluorescence, and immunoprecipitation assays. In vivo, colitis was induced by oral administration of DSS in drinking water, and peritonitis was induced by an intraperitoneal injection of alum. Recombinant adeno-associated virus (AAV serotype 9) vector was used to establish ZFP91 knockdown mouse. RESULTS: We confirmed that panaxadiol inhibited IL-1ß secretion by suppressing ZFP91 in macrophages. Further analysis revealed that panaxadiol inhibited IL-1ß secretion by suppressing ZFP91-regulated activation of non-canonical caspase-8 inflammasome. Meanwhile, panaxadiol inhibited IL-1ß secretion by suppressing ZFP91-regulated activation of MAPKs. In vivo, prominent anti-inflammatory effects of panaxadiol were demonstrated in a DSS induced acute colitis mouse model and in an alum-induced peritonitis model by suppressing ZFP91-regulated secretion of inflammatory mediators, consistent with the results of the AAV-ZFP91 knockdown in mice. CONCLUSIONS: We report for the first time that panaxadiol inhibited IL-1ß secretion by suppressing ZFP91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs, providing evidence for anti-inflammation mechanism of panaxadiol treatment for inflammatory diseases.

Zinc finger protein 91 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation.

Necroptosis is a form of regulated programmed cell death that is mediated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting serine/threonine protein kinase-3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL); however, it is not known whether zinc finger protein 91 (ZFP91) is involved in this process. Here, we investigated ZFP91 as a potential mediator of necroptosis. Our mechanistic study demonstrates that ZFP91 promotes RIPK1-RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. ZFP91 stabilized RIPK1 to promote cell death by inducing RIPK1 de-ubiquitination. ZFP91 also significantly increased production of mitochondrial reactive oxygen species (ROS). Accumulation of ROS promoted RIPK3-independent necroptosis triggered by tumor necrosis factor (TNF). in vivo, ZFP91 knockdown alleviated TNFα-induced systemic inflammatory response syndrome (SIRS). These results provide direct evidence that ZFP91 plays an important role in the initiation of RIPK1/RIPK3-dependent necroptosis in vitro and in vivo. We discussed the potential of ZFP91 as a novel therapeutic target for necroptosis-associated diseases.

MiR-302a Limits Vascular Inflammation by Suppressing Nuclear Factor-κ B Pathway in Endothelial Cells.

The inflammatory response of endothelial cells accelerates various vascular diseases. MicroRNAs (miRNAs) participate in diverse cellular processes during inflammation. In the present study, we found that miR-302a is an effective suppressor of vascular inflammation in endothelial cells. It was revealed that miR-302a exhibited a lower level in a lipopolysaccharide (LPS)-induced mouse model and in patients with vascular inflammatory disease. Genetic haploinsufficiency of miR-302 aggravated the LPS-induced vascular inflammatory response in mice, and overexpression of miR-302a attenuated vascular inflammation in mice. Furthermore, overexpression of miR-302a inhibited the synthesis and secretion of adhesion factors in endothelial cells, and suppressed the adhesion of monocytes to endothelium. In the study of molecular mechanism, we found that miR-302a relieved vascular inflammation mainly by regulating the nuclear factor kappa-B (NF-κB) pathway in endothelial cells. The results showed that interleukin-1 receptor-associated kinase4 (IRAK4) and zinc finger protein 91 (ZFP91) were the binding targets of miR-302a. MiR-302a prevented the nuclear translocation of NF-κB by inhibiting phosphorylation of IκB kinase complex ß (IKKß) and inhibitors of κBα (IκBα) via targeting IRAK4. In addition, miR-302a downregulated the expression of NF-κB by directly binding with ZFP91. These findings indicate that miR-302a negatively regulates inflammatory responses in the endothelium via the NF-κB pathway and it may be a novel target for relieving vascular inflammation.

Tumor suppressor lnc-CTSLP4 inhibits EMT and metastasis of gastric cancer by attenuating HNRNPAB-dependent Snail transcription.

Tumor metastasis is a crucial impediment to the treatment of gastric cancer (GC), and the epithelial-to-mesenchymal transition (EMT) program plays a critical role for the initiation of GC metastasis. Thus, the aim of this study is to investigate the regulation of lnc-CTSLP4 in the EMT process during GC progression. We found that lnc-CTSLP4 was significantly downregulated in GC tumor tissues compared with adjacent non-tumor tissues, and its levels in GC tumor tissues were closely correlated with tumor local invasion, TNM stage, lymph node metastasis, and prognosis of GC patients. Loss- and gain-of-function assays indicated that lnc-CTSLP4 inhibited GC cell migration, invasion, and EMT in vitro, as well as peritoneal dissemination in vivo. Mechanistic analysis demonstrated that lnc-CTSLP4 could bind with Hsp90α/heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) complex and recruit E3-ubiquitin ligase ZFP91 to induce the degradation of HNRNPAB, thus suppressing the transcriptional activation of Snail and ultimately reversing EMT of GC cells. Taken together, our results suggest that lnc-CTSLP4 is significantly downregulated in GC tumor tissues and inhibits metastatic potential of GC cells by attenuating HNRNPAB-dependent Snail transcription via interacting with Hsp90α and recruiting E3 ubiquitin ligase ZFP91, which shows that lnc-CTSLP4 could serve as a prognostic biomarker and therapeutic target for metastatic GC.

MicroRNA­188­5p inhibits the progression of breast cancer by targeting zinc finger protein 91.

Breast cancer (BC) is the most commonly diagnosed malignant cancer in women. BC is the main cause of cancer­related death in women and seriously threatens the life and health of women worldwide. MicroRNAs (miRNAs/miRs) have been reported to regulate the development and progression of different types of cancer. However, the regulatory functions of miR­188­5p in BC have not been thoroughly demonstrated. In this present research, we identified that miR­188­5p was downregulated in BC tissues and several BC cell lines. Downregulation of miR­188­5p was significantly associated with advanced TNM stage. Moreover, we identified that miR­188­5p mimics significantly inhibited proliferation using CCK­8 assay, colony formation and xenograft animal model, suppressed invasion and migration detected by Transwell invasion assay, and increased the cellular apoptosis of BC cells as determined by cell apoptosis assay. Moreover miR­188­5p mimics also reduced the expression of NF­κB p65(Rel). To further investigate its regulatory mechanism, transcription factor zinc finger protein 91 (ZFP91) was predicted as the targeted protein of miR­188­5p by bioinformatic method. We confirmed their specific binding by dual luciferase (DLR) assay. We demonstrated that the overexpression of miR­188­5p significantly inhibited the expression of ZFP91 in BC cell lines and reduced the expression of NF­κB p65(Rel). An inverse correlation was found between the expression of miR­188­5p and ZFP91 in BC tissues. Importantly, we demonstrated that the restoration of ZFP91 was able to block the effect of miR­188­5p on the progression of MDA­MB­231 cells. Therefore, our study showed that miR­188­5p may be one of the important indicators and could inhibit the progression of human BC via targeting the ZFP91/NF­κB p65(Rel) signaling pathway, suggesting that miR­188­5p may be a promising future target for BC treatment.

Overexpression of lncRNA Gm43050 alleviates apoptosis and inflammation response induced by sevoflurane treatment by regulating miR-640/ZFP91.

AIMS: The present study investigated the function and mechanism of lncRNA Gm43050 in sevoflurane-induced abnormal cognition. METHODS: Primary hippocampal neurons were used to establish the model of abnormal cognitive disorder. Overexpression and knockdown experiments were performed to analyze cell death rates, proliferation, apoptosis and the inflammatory response. The dual-luciferase reporter assay was used to analyze the potential binding targets of lncRNA Gm43050. Rescue experiments were used to assess the downstream targets of Gm43050. RESULTS: We found that lncRNA Gm43050 was in the cytoplasm. Overexpression of lncRNA Gm43050 had no impact on proliferation but significantly reduced the cell death rates and apoptosis. The inflammation markers IL-6, IL-1ß, IL-8 and TNF-α were manifestly downregulated in the overexpression group. Opposite effects were detected in the lncRNA Gm43050 knockdown group. Bioinformatics analysis showed that miR-640 may be the potential target of Gm43050. Additionally, we found that ZFP91 was the downstream target of miR-640. CONCLUSION: We provided comprehensive data of the function and mechanism of lncRNA Gm43050 in abnormal cognition. Our study showed that lncRNA Gm43050 exerted its important role via the regulation of miR-640 and ZFP91.

E3 ligase ZFP91 inhibits Hepatocellular Carcinoma Metabolism Reprogramming by regulating PKM splicing.

Rationale: Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and few molecularly targeted anticancer therapies have been developed to treat it. Thus, the identification of new therapeutic targets is urgent. Metabolic reprogramming is an important hallmark of cancer. However, how ubiquitin ligases are involved in the regulation of cancer metabolism remains poorly understood. Methods: RT-PCR, western blot and IHC were used to determine ZFP91 expression. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of ZFP91. Mouse xenograft models were used to study the in vivo effects of ZFP91. Co-IP together with mass spectrometry or western blot was utilized to investigate protein-protein interaction. Ubiquitination was analyzed using IP together with western blot. RNA splicing was assessed by using RT-PCR followed by restriction digestion. Lactate production and glucose uptake assays were used to analyze cancer metabolism. Results: We identified that an E3 ligase zinc finger protein 91 (ZFP91) suppressed HCC metabolic reprogramming, cell proliferation and metastasis in vitro and in vivo. Mechanistically, ZFP91 promoted the Lys48-linked ubiquitination of the oncoprotein hnRNP A1 at lysine 8 and proteasomal degradation, thereby inhibiting hnRNP A1-dependent PKM splicing, subsequently resulting in higher PKM1 isoform formation and lower PKM2 isoform formation and suppressing HCC glucose metabolism reprogramming, cell proliferation and metastasis. Moreover, HCC patients with lower levels of ZFP91 have poorer prognoses, and ZFP91 is an independent prognostic factor for patients with HCC. Conclusions: Our study identifies ZFP91 as a tumor suppressor of hepatocarcinogenesis and HCC metabolism reprogramming and proposes it as a novel prognostic biomarker and therapeutic target of HCC.

lncRNA MALAT1 modulates oxaliplatin resistance of gastric cancer via sponging miR-22-3p.

OBJECTIVE: Various regulatory mechanisms have been demonstrated to be associated with cancer progression. ncRNA and mRNA play important roles in gastric cancer (GC) cell growth and drug resistance, respectively. However, the regulatory network of ncRNA and mRNA in GC oxaliplatin (OXA) resistance has not been fully clarified. METHODS: The expression of miR-22-3p, MALAT1, and zinc finger protein 91 (ZFP91) was detected in tissues and cells using quantitative real-time PCR. The protein level of ZFP91 was measured by Western blot analysis. Luciferase reporter, pull-down, and RNA immunoprecipitation assays were used to determine the relationship between MALAT1, miR-22-3p, and ZFP91. MTT assay was applied to measure cell survival and proliferation. Cell apoptosis was detected using flow cytometry. Tumor xenograft assay was used to detect the function of miR-22-3p in vivo. RESULTS: In this study, we found that MALAT1 and ZFP91 expression was upregulated while the expression of miR-22-3p was downregulated in GC/OXA tissues and cells. Additionally, miR-22-3p was a target miRNA of MALAT1 and ZFP91 was a target mRNA of miR-22-3p. Functional studies showed that the knockdown of MALAT1 or overexpression of miR-22-3p inhibited GC/OXA cell survival, proliferation, and drug resistance as well as induced apoptosis, which could be reversed by the inhibition of miR-22-3p or overexpression of ZFP91. CONCLUSION: We observed a new regulatory network for MALAT1 in drug resistance of GC. MALAT1 modulates ZFP91 to promote GC cells OXA resistance via sponging miR-22-3p.

Long noncoding RNA SBF2-AS1 act as a ceRNA to modulate cell proliferation via binding with miR-188-5p in acute myeloid leukemia.

LncRNA SBF2-AS1 has been reported to be implicated in the deterioration of multiple human cancers. However, the roles and underlying mechanisms of SBF2-AS1 in acute myeloid leukemia (AML) are still unclear. In the present study, the online GEPIA database showed that SBF2-AS1 expression was significantly increased in AML samples. QRT-PCR results showed that SBF2-AS1 expression was upregulated in AML cells. CCK-8 assay revealed that SBF2-AS1 inhibition decreased AML cells proliferation ability in vitro. Flow cytometry assays showed that SBF2-AS1 inhibition induced AML cells apoptosis and arrested AML cells in G0/G1 phase. Mechanistically, miR-188-5p was identified as a direct target of SBF2-AS1. SBF2-AS1 upregulated the expression level of ZFP91 by sponging miR-188-5p. And the effects of SBF2-AS1 suppression on AML cells progression could be abolished by miR-188-5p inhibitors. Moreover, we found that SBF2-AS1 inhibition reduced tumor growth in vivo. Taken together, our findings elucidated that SBF2-AS1 could act as a miRNA sponge in AML progression, and provided a potential therapeutic strategy for AML treatment.

Zinc finger protein 91 (ZFP91) activates HIF-1α via NF-κB/p65 to promote proliferation and tumorigenesis of colon cancer.

Zinc finger protein 91 (ZFP91) has been reported to be involved in various biological processes. However, the clinical significance and biological role of ZFP91 in colon cancer remains unknown. Here, we show that ZFP91 expression is upregulated in patients with colon cancer. We found that ZFP91 upregulated HIF-1α at the levels of promoter and protein in colon cancer cells. Using chromatin immunoprecipitation, electrophoretic mobility shift assay and luciferase reporter gene assay, we found that NF-κB/p65 is required for the binding of ZFP91 to the HIF-1α promoter at -197/-188 base pairs and for the transcriptional activation of HIF-1α gene mediated by ZFP91. Flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU) incorporation and tumor xenograft assay demonstrated that ZFP91 enhanced cell proliferation of colon cancer through upregulating HIF-1α in vitro and in vivo. Furthermore, ZFP91 is positively associated with HIF-1α in human colon cancer. Thus, we concluded that ZFP91 activates transcriptional coregulatory protein HIF-1α through transcription factor NF-κB/p65 in the promotion of proliferation and tumorigenesis in colon cancer cell. ZFP91 may serve as a driver gene to activate HIF-1α transcription in the development of cancer.