Insulin-like Growth Factor 2 mRNA-binding Protein 1 Research Articles

The RNA-binding protein IMP2 drives a stromal-Th17 cell circuit in autoimmune neuroinflammation.

Stromal cells are emerging as key drivers of autoimmunity, partially because they produce inflammatory chemokines that orchestrate inflammation. Chemokine expression is regulated transcriptionally but also through posttranscriptional mechanisms, the specific drivers of which are still incompletely defined. CCL2 (MCP1) is a multifunctional chemokine that drives myeloid cell recruitment. During experimental autoimmune encephalomyelitis (EAE), an IL-17–driven model of multiple sclerosis, CCL2 produced by lymph node (LN) stromal cells was essential for immunopathology. Here, we showed that Ccl2 mRNA upregulation in human stromal fibroblasts in response to IL-17 required the RNA-binding protein IGF-2 mRNA-binding protein 2 (IGF2BP2, IMP2), which is expressed almost exclusively in nonhematopoietic cells. IMP2 binds directly to CCL2 mRNA, markedly extending its transcript half-life, and is thus required for efficient CCL2 secretion. Consistent with this, Imp2−/− mice showed reduced CCL2 production in LNs during EAE, causing impairments in monocyte recruitment and Th17 cell polarization. Imp2–/– mice were fully protected from CNS inflammation. Moreover, deletion of IMP2 after EAE onset was sufficient to mitigate disease severity. These data showed that posttranscriptional control of Ccl2 in stromal cells by IMP2 was required to permit IL-17–driven progression of EAE pathogenesis.

Hsa_circ_0001756 promotes ovarian cancer progression through regulating IGF2BP2-mediated RAB5A expression and the EGFR/MAPK signaling pathway

ABSTRACT Hsa_circ_0001756 was reported to be upregulated in serum samples of ovarian cancer (OC) patients and may serve as a potential OC biomarker. This study aimed to investigate the role and molecular mechanisms of hsa_circ_0001756 in OC procession. Herein, we detected the expression of hsa_circ_0001756 in OC tissues and cell lines with RT-qPCR assay, which showed that hsa_circ_0001756 was upregulated in OC tissues and cell lines. Then small interfering RNA targeting hsa_circ_0001756 (si-hsa_circ_0001756) was transfected into SKOV3 and A2780 cells, and the proliferation, invasion, and expression of epithelial-mesenchymal transition (EMT) marker proteins were determined with CCK-8, Transwell and Western blotting assays, respectively. We found that hsa_circ_0001756 knockdown inhibited OC cell proliferation, invasion and EMT. Moreover, RNA pull-down assay verified the binding between hsa_circ_0001756 and IGF2 mRNA binding protein 2 (IGF2BP2), and rescue experiments indicated that IGF2BP2 overexpression reversed the effects of has_circ_0001756 knockdown on OC cell functions. Co-IP assay verified IGF2BP2 could interact with RAB GTPase 5A (RAB5A) protein. Then SKOV3 cells were transfected with si-IGF2BP2 alone or together with pcDNA-RAB5A, followed by the detection of SKOV3 cell functions. We found that IGF2BP2 knockdown inhibited OC cell proliferation, invasion, and EMT, while RAB5A overexpression reversed these effects. Finally, SKOV3 cells transfected with si-hsa_circ_0001756 were injected into nude mice through tail vein. Hsa_circ_0001756 knockdown significantly inhibited the xenograft tumor growth of OC in vivo. In conclusion, hsa_circ_0001756 knockdown inhibits OC cell proliferation, invasion, and EMT, and reduces xenograft tumor growth by suppressing IGF2BP2-mediated RAB5A expression and blocking the EGFR/MAPK signaling pathway.

Expression profile, clinical significance and biological functions of IGF2BP2 in esophageal squamous cell carcinoma.

The ectopic expression of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) has been demonstrated to facilitate tumorigenesis and induce proliferation in a various types of cancer. However, the role of IGF2BP2 in esophageal squamous cell carcinoma (ESCC) has yet been fully elucidated. In this regard, the current study assessed the expression patterns and clinical significance of IGF2BP2 in 94 Chinese patients diagnosed with ESCC. Immunohistochemistry and reverse transcription-quantitative PCR assays were employed to assess IGF2BP2 expression in ESCC tissues compared with adjacent healthy tissues. The results revealed that the protein expression of IGF2BP2 was substantially upregulated in ESCC tissues compared with adjacent ESCC tissues. More specifically, higher IGF2BP2 expression strongly associated with tumor node metastasis stage, lymphatic infiltration and lymph node metastasis. Using two ESCC cell lines (TE-1 and TE-10), the inhibition of IGF2BP2 expression by small interfering RNA was proven to induce apoptosis and suppress proliferation, migration and cell cycle progression in vitro. Collectively, the present findings indicated that IGF2BP2 may serve a major role in the development of ESCC carcinogenesis. The present study may be helpful in the design of potential drug targets in the treatment of ESCC.

IGF2BP2-dependent activation of ERBB2 signaling contributes to acquired resistance to tyrosine kinase inhibitor in differentiation therapy of radioiodine-refractory papillary thyroid cancer.

Acquired drug resistance represents a major obstacle to tyrosine kinase inhibitor (TKI)-induced differentiation therapy of radioiodine-refractory papillary thyroid cancer (RR-PTC); thus, there is an urgent need to elucidate the underlying mechanisms. Here, selumetinib-resistant PTC (PTCSR) cell lines, which were characterized by loss of sodium/iodide symporter expression, enhanced insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), and activated V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) signaling, were initially established using a dose escalation method. Upon knockdown of IGF2BP2 in PTCSR cells, ERBB2 signaling was inhibited, and the acquired drug resistance was partially reversed. Mechanistically, the luciferase activity assay showed that IGF2BP2 bound to the N6-methyladenosine-binding site in the coding sequence of ERBB2 mRNA, yielding an increased ERBB2 translation efficacy revealed by polysome profiling. Inhibition of ERBB2 and IGF2BP2 by lapatinib robustly rescued the PTCSR cells from acquired dedifferentiation. Our study demonstrated that IGF2BP2-dependent ERBB2 signaling activation contributes to acquired resistance to TKI, which may be a promising differentiation strategy for RR-PTC by targeting IGF2BP2.

LncRNA LINC01134 Contributes to Radioresistance in Hepatocellular Carcinoma by Regulating DNA Damage Response via MAPK Signaling Pathway.

Hepatocellular carcinoma (HCC) is a highly mortal cancer that could be treated by radiotherapy. DNA damage response (DDR) is a vital factor affecting cancer development after radiotherapy. Long non-coding RNAs (lncRNAs) have been revealed to regulate DNA damage response and repair in cancer cells. Nevertheless, the function of long intergenic non-protein coding RNA 1134 (LINC01134) has not been explored in DDR. In this study, we targeted digging into the function of LINC01134 in DDR and exploring the underlying mechanism in HCC cells. RT-qPCR was employed to measure LINC01134 expression, and we found LINC01134 was significantly upregulated in HCC cells. Functional analysis suggested that LINC01134 depletion attenuated radioresistance of HCC cells by facilitating DNA damage. In vivo assays demonstrated LINC01134 depletion hindered HCC tumor growth. Mechanism assays unveiled LINC01134 sequestered microRNA-342-3p (miR-342-3p) and recruited insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) protein to modulate mitogen-activated protein kinase 1 (MAPK1) expression, consequently activating MAPK signaling pathway. Rescue assays validated the LINC01134/miR-342-3p/MAPK1 axis in the radio-resistant HCC cells. In conclusion, LINC01134 might be identified to be a useful biomarker for the therapy of HCC.

IGF2BP2 Induces U251 Glioblastoma Cell Chemoresistance by Inhibiting FOXO1-Mediated PID1 Expression Through Stabilizing lncRNA DANCR.

Glioma is the most common type of malignant tumor of the nervous system and is characterized by high mortality and poor outcome. This study aims to investigate the mechanism underlying IGF2 mRNA-binding protein 2 (IGF2BP2) and long noncoding RNA DANCR in etoposide resistance of glioblastoma (GBM) cells. Bioinformatics analysis identified the IGF2BP2-related regulators and DANCR target genes, which were subsequently evaluated by RNA pull-down and RIP assays. We exposed GBM cells to etoposide and thus established etoposide-resistant cells. Through functional experiments, we evaluated the interrelationship among IGF2BP2, DANCR, phosphotyrosine interaction domain containing 1 (PID1), and forkhead box protein O1 (FOXO1) and further assessed their impact on the sensitivity of GBM cells to etoposide. IGF2BP2 and DANCR were highly expressed in glioma cells and tissues, whereas PID1 and FOXO1 were poorly expressed. Mechanistically, overexpression of IGF2BP2 promoted DANCR stability and reduced DANCR methylation, whereas silencing of IGF2BP2 reduced survival of GBM cells and etoposide-resistant cells. Besides, DANCR interacted with FOXO1 to promote the ubiquitination of FOXO1. FOXO1 promoted the transcriptional expression of PID1, enhancing the chemotherapy sensitivity of GBM cells, but overexpression of PID1 reversed the impact of IGF2BP2. Collectively, IGF2BP2 inhibits PID1 expression through the DANCR/FOXO1 axis, inducing drug resistance in GBM cells, and promoting glioma progression.

IGF2BP2 Regulates MALAT1 by Serving as an N6-Methyladenosine Reader to Promote NSCLC Proliferation.

Insulin-like growth factor 2 (IGF2) mRNA-binding protein 2 (IGF2BP2) is an important posttranscriptional regulatory for stability and m6A modification. Here, we investigated the role of IGF2BP2 in non–small-cell lung cancer (NSCLC) proliferation. TCGA database was used to predict the expression and clinical significance of IGF2BP2 in normal and NSCLC samples. The expression of IGF2BP2 was further validated in NSCLC samples from surgery. Then we performed the functional study in NSCLC cell lines through overexpressing and knocking down IGF2BP2 in NSCLC cell lines in vitro and in vivo. The mechanism of interaction between IGF2BP2 and lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in NSCLC proliferation was determined by RIP assay. We demonstrated that IGF2BP2 is highly expressed in NSCLC and positively associated with poor overall survival (OS) and disease-free survival (DFS). We identified that lncRNA MALAT1 is a target of IGF2BP2 in NSCLC. IGF2BP2 promotes MALAT1 stability in an m6A-dependent mechanism, thus promoting its downstream target autophagy-related (ATG)12 expression and NSCLC proliferation.

EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3

BackgroundGliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours.MethodsCircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted.ResultsWe identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression.ConclusionsThis work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.

Insulin-like growth factor 2 mRNA-binding protein 2-stabilized long non-coding RNA Taurine up-regulated gene 1 (TUG1) promotes cisplatin-resistance of colorectal cancer via modulating autophagy

ABSTRACT Long non-coding RNAs (lncRNAs) have been demonstrated to influence the chemoresistance of colorectal cancer (CRC). Therefore, the study is designed to investigate the regulatory function and mechanism of Taurine up-regulated gene 1 (TUG1) in the cisplatin resistance of CRC. qRT-PCR checked the expressions of TUG1, Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), and miR-195-5p in CRC tissues and cells. The TUG1 or miR-195-5p overexpression model was engineered in CRC cells, followed by treatment with DDP or the autophagy inhibitor (Chloroquine, CQ). CCK8 (Cell Counting Kit-8) and the colony formation experiment monitored cell proliferation. Flow cytometry examined apoptosis, Transwell tracked migration and invasion, and Western blot ascertained the protein profiles of autophagy proteins (LC3I/LC3II and Beclin1) and the HDGF/DDX5/β-catenin pathway. Dual-luciferase gene reporter assay and RNA immunoprecipitation confirmed the binding correlation between TUG1 and miR-195-5p and between miR-195-5p and HDGF. Furthermore, in-vivo experiments in nude mice probed the function and mechanism of IGF2BP2 in CRC cell growth. The profiles of TUG1 and IGF2BP2 were elevated in CRC tissues, and IGF2BP2 enhanced TUG1’s expression in CRC cells. TUG1 activated autophagy to facilitate CRC cells’ resistance to DDP. TUG1 targets miR-195-5p, and miR-195-5p targets HDGF. Overexpression of miR-195-5p abated the cancer-promoting function of TUG1 and curbed the profile of the HDGF/DDX5/β-catenin axis. TUG1 stabilized by IGF2BP2 boosted CRC cell proliferation, migration, migration, and autophagy via the miR-195-5p/HDGF/DDX5/β-catenin axis, hence enhancing CRC cell’s resistance to DDP.

Deficiency of lncRNA SNHG12 impairs ischemic limb neovascularization by altering an endothelial cell cycle pathway.

SNHG12, a long noncoding RNA (lncRNA) dysregulated in atherosclerosis, is known to be a key regulator of vascular senescence in endothelial cells (ECs). However, its role in angiogenesis and peripheral artery disease has not been elucidated. Hind-limb ischemia studies using femoral artery ligation (FAL) in mice showed that SNHG12 expression falls readily in the acute phase of the response to limb ischemia in gastrocnemius muscle and recovers to normal when blood flow recovery is restored to ischemic muscle, indicating that it likely plays a role in the angiogenic response to ischemia. Gain- and loss-of-function studies demonstrated that SNHG12 regulated angiogenesis — SNHG12 deficiency reduced cell proliferation, migration, and endothelial sprouting, whereas overexpression promoted these angiogenic functions. We identified SNHG12 binding partners by proteomics that may contribute to its role in angiogenesis, including IGF-2 mRNA–binding protein 3 (IGF2BP3, also known as IMP3). RNA-Seq profiling of SNHG12-deficient ECs showed effects on angiogenesis pathways and identified a strong effect on cell cycle regulation, which may be modulated by IMP3. Knockdown of SNHG12 in mice undergoing FAL using injected gapmeRs) decreased angiogenesis, an effect that was more pronounced in a model of insulin-resistant db/db mice. RNA-Seq profiling of the EC and non-EC compartments in these mice revealed a likely role of SNHG12 knockdown on Wnt, Notch, and angiopoietin signaling pathways. Together, these findings indicate that SNHG12 plays an important role in the angiogenic EC response to ischemia.

The cancer-testis lncRNA lnc-CTHCC promotes hepatocellular carcinogenesis by binding hnRNP K and activating YAP1 transcription.

Cancer-testis (CT) genes participate in the initiation and progression of cancer, but the role of CT-associated long non-coding RNAs (CT-lncRNAs) in hepatocellular carcinoma (HCC) is still elusive. Here, we discovered a conserved CT-lncRNA, named lnc-CTHCC, which was highly expressed in the testes and HCC. A lnc-CTHCC-knockout (KO) mouse model further confirmed that the global loss of lnc-CTHCC inhibited the occurrence and development of HCC. In vitro and in vivo assays also showed that lnc-CTHCC promoted HCC growth and metastasis. Mechanistically, lnc-CTHCC bound to heterogeneous nuclear ribonucleoprotein K (hnRNP K), which was recruited to the YAP1 promoter for its activation. Additionally, the N6-methyladenosine (m6A) modification was mediated by N6-adenosine-methyltransferase 70-kDa subunit (METTL3) and recognized by insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)/IGF2BP3, which maintained lnc-CTHCC stability and increased its expression in HCC. Together, our results show that lnc-CTHCC directly binds to hnRNP K and promotes hepatocellular carcinogenesis and progression by activating YAP1 transcription, suggesting that lnc-CTHCC is a potential biomarker and therapeutic target of HCC.

FOXP3 activated-LINC01232 accelerates the stemness of non-small cell lung carcinoma by activating TGF-β signaling pathway and recruiting IGF2BP2 to stabilize TGFBR1

Non-small cell lung carcinoma (NSCLC) is one of the most common malignant tumors worldwide with high incidence and mortality. Long non-coding RNAs (lncRNAs) have been reported to affect human cancer progression. The present study aimed to investigate the regulatory role and mechanism of long intergenic non-protein coding RNA 1232 (LINC01232) in NSCLC cells. RT-qPCR results revealed that LINC01232 expression was high in NSCLC cells. Flow cytometry and sphere formation assays indicated that LINC01232 significantly promoted NSCLC cell stemness. Luciferase reporter assay and ChIP assay validated that forkhead box P3 (FOXP3) could bind to LINC01232 promoter and activate LINC01232 transcription. Further, LINC01232 was certified to activate TGF-β signaling pathway through regulating transforming growth factor beta receptor 1 (TGFBR1). After RIP and RNA pull down assays, insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) was proven as the RNA-binding protein (RBP) for LINC01232. LINC01232 promoted TGFBR1 mRNA stability via recruiting IGF2BP2. Subsequently, LINC01232 was verified to accelerate NSCLC cell stemness and induce macrophage M2 polarization via upregulating TGFBR1. Taken together, FOXP3 activated-LINC01232 accelerated NSCLC cell stemness by activating TGF-β signaling pathway and recruiting IGF2BP2 to stabilize TGFBR1, which might offer a rationale for lncRNA-based treatment to NSCLC.

Hsa_circ_0003258 promotes prostate cancer metastasis by complexing with IGF2BP3 and sponging miR-653-5p

BackgroundMore and more studies have shown that circular RNAs (circRNAs) play a critical regulatory role in many cancers. However, the potential molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unknown.MethodsDifferentially expressed circRNAs were identified by RNA sequencing. The expression of hsa_circ_0003258 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of hsa_circ_0003258 on the metastasis of PCa cells were investigated by a series of in vitro and in vivo assays. Lastly, the underlying mechanism of hsa_circ_0003258 was revealed by Western blot, biotin-labeled RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments.ResultsIncreased expression of hsa_circ_0003258 was found in PCa tissues and was associated with advanced TNM stage and ISUP grade. Overexpression of hsa_circ_0003258 promoted PCa cell migration by inducing epithelial mesenchymal transformation (EMT) in vitro as well as tumor metastasis in vivo, while knockdown of hsa_circ_0003258 exerts the opposite effect. Mechanistically, hsa_circ_0003258 could elevate the expression of Rho GTPase activating protein 5 (ARHGAP5) via sponging miR-653-5p. In addition, hsa_circ_0003258 physically binds to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) in the cytoplasm and enhanced HDAC4 mRNA stability, in which it activates ERK signalling pathway, then triggers EMT programming and finally accelerates the metastasis of PCa.ConclusionsUpregulation of hsa_circ_0003258 drives tumor progression through both hsa_circ_0003258/miR-653-5p/ARHGAP5 axis and hsa_circ_0003258/IGF2BP3 /HDAC4 axis. Hsa_circ_0003258 may act as a promising biomarker for metastasis of PCa and an attractive target for PCa intervention.

METTL3-mediated m6A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy

Epigenetic changes are present in many physiological and pathological processes. The N6-methyladenosine (m6A) modification is the most common modification in eukaryotic mRNA. However, the role of m6A modification in diabetic nephropathy (DN) remains elusive. Here, we found that m6A modification was significantly upregulated in the kidney of type 1 and type 2 diabetic mice, which was caused by elevated levels of METTL3. Moreover, METTL3 is increased in podocyte of renal biopsy from patients with DN, which is related to renal damage. METTL3 knockout significantly reduced the inflammation and apoptosis in high glucose (HG)-stimulated podocytes, while its overexpression significantly aggravated these responses invitro. Podocyte-conditional knockout METTL3 significantly alleviated podocyte injury and albuminuria in streptozotocin (STZ)-induced diabetic mice. Therapeutically, silencing METTL3 with adeno-associated virus serotype-9 (AAV9)-shMETTL3 invivo mitigated albuminuria and histopathological injury in STZ-induced diabetic mice and db/db mice. Mechanistically, METTL3 modulated Notch signaling via the m6A modification of TIMP2 in an insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2)-dependent manner and exerted pro-inflammatory and pro-apoptotic effects. In summary, this study suggested that METTL3-mediated m6A modification is an important mechanism of podocyte injury in DN. Targeting m6A through the writer enzyme METTL3 is a potential approach for the treatment of DN.

Cytoplasmic IGF2BP2 Protein Expression in Human Patients with Oral Squamous Cell Carcinoma: Prognostic and Clinical Implications.

Oral squamous cell carcinoma (OSCC) is particularly prevalent in Taiwan. The goal of this study was to determine the clinicopathological role of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) proteins as an indicator of clinical outcomes in OSCC patients. In this study, immunohistochemical (IHC) analysis was used to examine IGF2BP2 protein expression in 244 OSCC patients. We investigated the relationships among IGF2BP2 expression, clinicopathological variables, and patient survival. Our results showed that IGF2BP2 cytoplasmic protein expression was significantly correlated with lymph node metastasis, cancer stage, and patient survival. Kaplan-Meier survival curves revealed that elevated cytoplasmic IGF2BP2 expression levels in OSCC patients were associated with poor overall survival. Moreover, multivariate cox proportional hazard models revealed that cytoplasmic IGF2BP2 expression, T status, and lymph node metastasis were independent prognostic factors for survival. In conclusion, IGF2BP2 protein was found to be a helpful predictive marker for OSCC patients, as well as a possible therapeutic target for OSCC treatment.

SP1-induced lncRNA MCF2L-AS1 promotes cisplatin resistance in ovarian cancer by regulating IGF2BP1/IGF2/MEK/ERK axis.

Cisplatin resistance is a huge problem encountered in ovarian cancer treatment. Our study probed the roles and the underlying mechanisms of lncRNA MCF2L-AS1 in ovarian cancer cisplatin-resistance. SKOV3 and IGROV-1 cells were subjected to gradually increasing concentrations of cisplatin to construct ovarian cancer cisplatin-resistance cells. Cell proliferation was evaluated by cell counting kit-8 and colony formation assays. Cell apoptosis was assessed using Annexin V and PI staining. The relationships between SP1, MCF2L-AS1 and insulin-like growth factor-2 mRNA binding protein 1 (IGF2BP1) were verified by RNA pull-down, RIP, ChIP and dual-luciferase reporter gene assay, respectively. Tumor xenograft experiment was employed to evaluate the effects of MCF2L-AS1 silencing on ovarian cancer cisplatin-resistance in vivo. TUNEL staining and immunohistochemistry were performed in tumor tissue. MCF2L-AS1 and IGF2BP1 were upregulated in cisplatin-resistant cells. MCF2L-AS1 silencing suppressed cell proliferation of cisplatin-resistant cells, while promoted the apoptosis, suggesting that MCF2L-AS1 knockdown suppressed ovarian cancer cells cisplatin-resistance. Meanwhile, MCF2L-AS1 silencing enhanced cisplatin sensitivity in ovarian cancer parental cells and IGF2BP1 overexpression impaired cisplatin sensitivity of parental cells. MCF2L-AS1 activated IGF2/MEK/ERK pathway through interacting with IGF2BP1. Transcription factor SP1 activated MCF2L-AS1 expression. MCF2L-AS1 knockdown inhibited ovarian cancer cisplatin-resistance in vivo. SP1-induced MCF2L-AS1 promoted ovarian cancer cisplatin-resistance through activation of IGF2/MEK/ERK pathway via interacting with IGF2BP1.

Involvement of m6A regulatory factor IGF2BP1 in malignant transformation of human bronchial epithelial Beas-2B cells induced by tobacco carcinogen NNK

Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a Group 1 human carcinogen, as classified by the International Agency for Research of Cancer (IARC), and plays a significant role in lung carcinogenesis. However, its carcinogenic mechanism has not yet been fully elucidated. In this study, we performed colony formation assays, soft-agar assays, and tumor growth in nude mice to show that 100 mg/L NNK facilitates the malignant transformation of human bronchial epithelial Beas-2B cells. Transcriptome sequencing showed that insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), a post-transcriptional regulator, was differentially expressed in NNK-induced malignant transformed Beas-2B cells (2B-NNK cells). Small interfering RNA (SiRNA) was used to downregulate the expression of the IGF2BP1 gene. The reduction in protein expression, cell proliferation rate, and colony-forming ability and the increase in the apoptosis rate of Beas-2B cells transfected with the SiRNA indicated a role for IGF2BP1 in NNK-induced malignant transformation. IGF2BP1 is an N6-methyladenosine (m6A) regulatory factor, but it is not known whether its association with m6A mediates the malignant transformation of cells. Therefore, we measured the overall levels of m6A in Beas-2B cells. We found that the overall m6A level was lower in 2B-NNK cells, and knocking down IGF2BP1, the overall level of m6A was restored. Hence, we concluded that IGF2BP1 is involved in the NNK-induced malignant transformation of Beas-2B cells, possibly via m6A modification. This study therefore contributes novel insights into the environmental pathogenesis of lung cancer and the gene regulatory mechanisms of chemical carcinogenesis.

RETRACTED ARTICLE: Long noncoding RNA UBA6-AS1 inhibits the malignancy of ovarian cancer cells via suppressing the decay of UBA6 mRNA

Statement of Retraction Yaogang Wang & Zhigao Chen (2022) Long noncoding RNA UBA6-AS1 inhibits the malignancy of ovarian cancer cells via suppressing the decay of UBA6 mRNA, Bioengineered, 13:1, 178-189, DOI: 10.1080/21655979.2021.2011640 Since publication, significant concerns have been raised about the integrity of the data and reported results in the article. When approached for an explanation, the authors did not provide their original data or any necessary supporting information. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The corresponding author listed in this publication has been informed. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Specific Regulation of m6A by SRSF7 Promotes the Progression of Glioblastoma

Serine/arginine-rich splicing factor 7 (SRSF7), a known splicing factor, has been revealed to play oncogenic roles in multiple cancers. However, the mechanisms underlying its oncogenic roles have not been well addressed. Here, based on N6-methyladenosine (m6A) co-methylation network analysis across diverse cell lines, we find that the gene expression of SRSF7 is positively correlated with glioblastoma (GBM) cell-specific m6A methylation. We then indicate that SRSF7 is a novel m6A regulator, which specifically facilitates the m6A methylation near its binding sites on the mRNAs involved in cell proliferation and migration, through recruiting the methyltransferase complex. Moreover, SRSF7 promotes the proliferation and migration of GBM cells largely dependent on the presence of the m6A methyltransferase. The two m6A sites on the mRNA for PDZ-binding kinase (PBK) are regulated by SRSF7 and partially mediate the effects of SRSF7 in GBM cells through recognition by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Together, our discovery reveals a novel role of SRSF7 in regulating m6A and validates the presence and functional importance of temporal- and spatial-specific regulation of m6A mediated by RNA-binding proteins (RBPs).

IGF2BP3 promotes cell metastasis and is associated with poor patient survival in nasopharyngeal carcinoma.

Metastasis contributes to treatment failure in nasopharyngeal carcinoma (NPC) patients. Our study aimed at elucidating the role of insulin‐like growth factor 2 mRNA binding protein 3 (IGF2BP3) in NPC metastasis and the underlying mechanism involved. IGF2BP3 expression in NPC was determined by bioinformatics, quantitative polymerase chain reaction and immunohistochemistry analyses. The biological function of IGF2BP3 was investigated by using in vitro and in vivo studies. In this study, IGF2BP3 mRNA and protein levels were elevated in NPC tissues. In addition, IGF2BP3 exerted an oncogenic role by promoting epithelial‐mesenchymal transition (EMT), thereby inducing NPC cell migration and invasion. Further studies revealed that IGF2BP3 regulated the expression of key regulators of EMT by activating AKT/mTOR signalling, thus stimulating NPC cell migration and invasion. Remarkably, targeting IGF2BP3 delayed NPC metastasis through attenuating p‐AKT and vimentin expression and inducing E‐cadherin expression in vivo. Moreover, IGF2BP3 protein levels positively correlated with distant metastasis after initial treatment. Importantly, IGF2BP3 expression served as an independent prognostic factor in predicting the overall survival and distant metastasis‐free survival of NPC patients. This work identifies IGF2BP3 as a novel prognostic marker and a new target for NPC treatment.