Accelerated Cell Proliferation Research Articles

Identification of PSMD2 as a promising biomarker for pancreatic cancer patients based on comprehensive bioinformatics and in vitro studies

BackgroundPancreatic cancer patients have limited treatment options and extremely poor prognosis. Dysregulations of proteasome 26S subunit, non-ATPases (PSMDs) contribute to the development of various cancers, whereas the significance of PSMDs in pancreatic cancer is poorly understood. In the present study, we intended to explore the therapeutic potential of PSMDs in pancreatic cancer. MethodsBased on TCGA database, the expression of PSMDs was analyzed in pancreatic cancer patients. Multivariate Cox regression and Kaplan–Meier survival analyses were conducted to investigate the prognostic value of PSMDs. The correlations between the expression of PSMD2/14 and immune cell infiltration, immune checkpoint genes’ expression, enrichment of signaling pathways, and the sensitivity of chemotherapies were also evaluated. Knockdown and overexpression experiments were performed to explore the biological function of PSMD2/14. Immunoblotting was conducted to detect the downstream signaling pathway of PSMD2. ResultsMost of the PSMDs, except for PSMD5 and PSMD6, were significantly upregulated in pancreatic cancer tissues. Patients with higher grade tumor had increased mRNA levels of PSMD1/2/5/7/8/11/12/14. Survival and multivariate Cox regression analyses indicated that PSMD2 and PSMD14 were biomarkers of worse prognosis. High expression of PSMD2 and PSMD14 was positively correlated with the levels immune checkpoint genes but not with the infiltration of specific immune cell types. In vitro knockdown of PSMD2, but not PSMD14, increased the apoptosis, gemcitabine’s toxicity and inhibited the growth capacity of MIA cells. Conversely, decreased apoptosis and gemcitabine sensitivity along with accelerated cell proliferation ability were observed in PSMD2-overexpressing PANC-1 cells. Mechanistically, PSMD2 activated the AKT/mTOR signaling pathway, consistent with the findings from KEGG and GSEA analysis. The AKT specific inhibitor MK-2206 exhibited higher cytotoxicity in MIA and PANC-1 cells with high PSMD2 expression. Importantly, MK-2206 largely reversed the oncogenic functions of PSMD2 on the growth and proliferation of PANC-1 cells. ConclusionIn summary, our study provided a comprehensive bioinformatics analysis of PSMDs in pancreatic cancer. We identified that PSMD2 acted as a tumor-promoting protein in pancreatic cancer through the activation of the AKT/mTOR pathway. The overexpression of PSMD2 may be a potential biomarker that predicts the response of pancreatic cancer patients to AKT inhibitor treatments.

E3 ubiquitin ligase DTX2 fosters ferroptosis resistance via suppressing NCOA4-mediated ferritinophagy in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) remains the foremost contributor to cancer-related fatalities globally, with limited effective therapeutic modalities. Recent research has shed light on the role of ferroptosis in various types of cancers, offering a potential avenue for improving cancer therapy. Herein, we identified E3 ubiquitin ligase deltex 2 (DTX2) as a potential therapeutic target candidate implicated in promoting NSCLC cell growth by inhibiting ferroptosis. Our investigation revealed a significant upregulation of DTX2 in NSCLC cells and tissues, which was correlated with poor prognosis. Downregulation of DTX2 suppressed NSCLC cell growth both in vitro and in vivo, while its overexpression accelerated cell proliferation. Moreover, knockdown of DTX2 promoted ferroptosis in NSCLC cells, which was mitigated by DTX2 overexpression. Mechanistically, we uncovered that DTX2 binds to nuclear receptor coactivator 4 (NCOA4), facilitating its ubiquitination and degradation via the K48 chain, which subsequently dampens NCOA4-driven ferritinophagy and ferroptosis in NSCLC cells. Notably, DTX2 knockdown promotes cisplatin-induced ferroptosis and overcomes drug resistance of NSCLC cells. These findings underscore the critical role of DTX2 in regulating ferroptosis and NCOA4-mediated ferritinophagy, suggesting its potential as a novel therapeutic target for NSCLC.

Double-Faced Immunological Effects of CDK4/6 Inhibitors on Cancer Treatment: Challenges and Perspectives

Cyclin-dependent kinases (CDKs) are generally involved in the progression of cell cycle and cell division in normal cells, while abnormal activations of CDKs are deemed to be a driving force for accelerating cell proliferation and tumorigenesis. Therefore, CDKs have become ideal therapeutic targets for cancer treatment. The U.S FDA has approved three CDK4/6 inhibitors (CDK4/6is) for the treatment of patients with hormone receptor-positive (HR+) or human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer, and these drugs showed impressive results in clinics. Besides cell-cycle arrest, there is growing evidence that CDK4/6is exert paradoxical roles on cancer treatment by altering the immune system. Indeed, clinical data showed that CDK4/6is could change the immune system to exert antitumor effects, while these changes also caused tumor resistance to CDK4/6i. However, the molecular mechanism for the regulation of the immune system by CDK4/6is is unclear. In this review, we comprehensively discuss the paradoxical immunological effects of CDK4/6is in cancer treatment, elucidating their anticancer mechanisms through immunomodulatory activity and induction of acquired drug resistance by dysregulating the immune microenvironment. More importantly, we suggest a few strategies including combining CDK4/6is with immunotherapy to overcome drug resistance.

RETINOBLASTOMA-RELATED Has Both Canonical and Noncanonical Regulatory Functions During Thermo-Morphogenic Responses in Arabidopsis Seedlings.

Warm temperatures accelerate plant growth, but the underlying molecular mechanism is not fully understood. Here, we show that increasing the temperature from 22°C to 28°C rapidly activates proliferation in the apical shoot and root meristems of wild-type Arabidopsis seedlings. We found that one of the central regulators of cell proliferation, the cell cycle inhibitor RETINOBLASTOMA-RELATED (RBR), is suppressed by warm temperatures. RBR became hyper-phosphorylated at a conserved CYCLIN-DEPENDENT KINASE (CDK) site in young seedlings growing at 28°C, in parallel with the stimulation of the expressions of the regulatory CYCLIN D/A subunits of CDK(s). Interestingly, while under warm temperatures ectopic RBR slowed down the acceleration of cell proliferation, it triggered elongation growth of post-mitotic cells in the hypocotyl. In agreement, the central regulatory genes of thermomorphogenic response, including PIF4 and PIF7, as well as their downstream auxin biosynthetic YUCCA genes (YUC1-2 and YUC8-9) were all up-regulated in the ectopic RBR expressing line but down-regulated in a mutant line with reduced RBR level. We suggest that RBR has both canonical and non-canonical functions under warm temperatures to control proliferative and elongation growth, respectively.

Transcription factor Nrf2 regulating the interaction of p16 facilitates hydroquinone-induced malignant transformation of TK6 cells by accelerating cell proliferation

The nuclear factor erythroid 2-related factor 2 (Nrf2) is overexpressed in multiple tumor cells. Nevertheless, the role of Nrf2 in malignant transformation induced by hydroquinone (HQ) is unknown. Here, we hypothesized that Nrf2 might participate in HQ-induced malignant transformation of TK6 cells, a line of normal human lymphoblastoid cells, by accelerating cell proliferation and regulating cell cycle progression. The data indicated that TK6 cells chronically exposed to HQ continuously activated Nrf2-Keap1 signaling pathway. Furthermore, we found that defects in Nrf2 inhibited cell proliferation and prevented cells from entering S phase from G1 phase. Mechanistically, Nrf2 is involved in cell cycle abnormalities induced by prolonged exposure to HQ by binding to p16, thereby activating the p16/Rb signaling pathway. Taken together, Nrf2 might be a potential driver of carcinogenesis that promotes malignant cell proliferation and affects cell cycle distribution.

PVA-gelatine based hydrogel loaded with astaxanthin and mesoporous bioactive glass nanoparticles for wound healing

Astaxanthin (AST) is a potent antioxidant phytochemical used in wound healing with promising results in-vitro. However, AST incorporation into clinical practice still faces challenges related to the susceptibility of AST to instability. One of the most innovative solutions proposed is the encapsulation of AST into hydrogels. This study focuses on innovating the wound healing potential of AST-containing hydrogels by introducing silicate mesoporous bioactive glass nanoparticles (MBGNs). These nanoparticles release biologically active ions that accelerate cell proliferation and migration. The results showcase an innovative synergistic effect between 1 μg/mL of AST with 100 μg/mL of MBGNs, outperforming the individual proliferation effect of AST or MBGNs alone. Separately, these compounds were encapsulated in physical and chemical cross-linked hydrogel for the compound protection and delivery, finding that PVA-gelatine hydrogels are a suitable matrix for the delivery of AST and MBGNs. Physically crosslinked hydrogels showed particularly convenient characteristics for potential clinical implementation while maintaining the synergetic effect of AST and MBGNs. Although chemically crosslinked hydrogels exhibited suitable characteristics as a vehicle for AST in biological assays, cell proliferation was reduced by 57 %. The results of this research open avenues for exploring the development of new composite matrices for the co-delivery of phytochemicals and MBGNs for cutting-edge biomedical applications.

Identification of a novel immune infiltration-related gene signature, MCEMP1, for coronary artery disease.

This study aims to identify a novel gene signature for coronary artery disease (CAD), explore the role of immune cell infiltration in CAD pathogenesis, and assess the cell function of mast cell-expressed membrane protein 1 (MCEMP1) in human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL). To identify differentially expressed genes (DEGs) of CAD, datasets GSE24519 and GSE61145 were downloaded from the Gene Expression Omnibus (GEO) database using the R "limma" package with p < 0.05 and |log2 FC| > 1. Gene ontology (GO) and pathway analyses were conducted to determine the biological functions of DEGs. Hub genes were identified using support vector machine-recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO). The expression levels of these hub genes in CAD were validated using the GSE113079 dataset. CIBERSORT program was used to quantify the proportion of immune cell infiltration. Western blot assay and qRT-PCR were used to detect the expression of hub genes in ox-LDL-treated HUVECs to validate the bioinformatics results. Knockdown interference sequences for MCEMP1 were synthesized, and cell proliferation and apoptosis were examined using a CCK8 kit and Muse® Cell Analyzer, respectively. The concentrations of IL-1β, IL-6, and TNF-α were measured with respective enzyme-linked immunosorbent assay (ELISA) kits. A total of 73 DEGs (four down-regulated genes and 69 up-regulated genes) were identified in the metadata (GSE24519 and GSE61145) cohort. GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results indicated that these DEGs might be associated with the regulation of platelet aggregation, defense response or response to bacterium, NF-kappa B signaling pathway, and lipid and atherosclerosis. Using SVM-RFE and LASSO, seven hub genes were obtained from the metadata. The upregulated expression of DIRC2 and MCEMP1 in CAD was confirmed in the GSE113079 dataset and in ox-LDL-treated HUVECs. The associations between the two hub genes (DIRC2 and MCEMP1) and the 22 types of immune cell infiltrates in CAD were found. MCEMP1 knockdown accelerated cell proliferation and suppressed cell apoptosis for ox-LDL-treated HUVECs. Additionally, MCEMP1 knockdown appeared to decrease the expression of inflammatory factors IL-1β, IL-6, and TNF-α. The results of this study indicate that MCEMP1 may play an important role in CAD pathophysiology.

Low-energy electric shock ameliorates cell proliferation, morphallaxis, and regeneration via driving key regenerative proteins in earthworm and 3T3 cells

Electric stimulation regulates many cellular processes like cell proliferation, differentiation, apoptosis and cellular migration. Despite its crucial role in regulating stem cells and regeneration, it remains underexplored in both in-vivo and in-vitro settings. In this study, Eudrilus eugeniae are subjected to electric stimulation (1.5 V) prior and after amputation and which augments regeneration up to double-time. Blocking epimorphosis using 2 M thymidine retracts regeneration kinetics to one-third but such inhibition was rescued by applying electric stimulation which propels an overactive morphallaxis pattern of regeneration. Excreting electric stimulation on control worms shows minimal impact, whereas it enhances the key regenerative proteins like VEGF, COX2, YAP, c-Myc, and Wnt3a on amputated worms. Upon blocking epimorphosis, all these key regenerative proteins are down-regulated but through electric stimulation, the cells are reprogrammed to express a triple fold of the mentioned regenerative proteins, that further promotes morphallaxis. In 3T3 cells, electric stimulation accelerates cell proliferation and migrations in 5 secs exposure and it exerts its function by overexpressing VEGF mediated by MEK1. Wnt3a expression was gradually upregulated in increasing exposure (5 and 25 secs) which aids in maintaining the stemness property. The molecular mechanism underlying regeneration capability can assist in designing novel therapeutic applications.

Multifaceted Understandings of Cancer: A Review of Disease Mechanisms and Therapies

Abstract: Cancer is a condition in which aberrant cells continue to divide uncontrollably, causing tissue to be destroyed. Different cancer stages have been identified by researchers, suggesting that a number of gene alterations are involved in the etiology of cancer. Unusual cell proliferation is brought on by these gene alterations. A crucial role in the acceleration of cell proliferation is played by genetic diseases brought on by heredity or hereditary factors. Its diagnosis and treatment have historically been regarded as two of the most important and significant clinical concerns. Depending on the nature and stage of the tumor, numerous ways to its corrective therapy have been established. Numerous biomolecules derived from plants are crucial for the treatment of the disease. In this review, we focus on specific aspects to give a brief overview of the major problems, including their etiology, therapies that are available, herbal alternates, available vaccines and relevant biomarkers. It was felt that much work needs to be done on combination therapy development and platform optimization.

Nanofiber-reinforced chitosan/gelatine hydrogel with photothermal, antioxidant and conductive capabilities promotes healing of infected wounds

The wound healing process was often accompanied by bacterial infection and inflammation. The combination of electrically conductive nanomaterials and wound dressings could accelerate cell proliferation through endogenous electrical signaling, effectively promoting wound healing. In this study, polypyrrole was modified with dopamine hydrochloride by an in situ polymerization to form dopamine-polypyrrole (DA-Ppy) conductive nanofibers which successfully enhanced the water dispersibility and biocompatibility of polypyrrole. The DA-Ppy nanofibers were dispersed in an aqueous solution for >48 h and still maintained good stability. In addition, the DA-Ppy nanofibers showed good photothermal properties, and the temperature could reach 59.7 °C by 1.5 W/cm2 near-infrared light irradiation (NIR) for 10 min. DA-Ppy conductive nanofibres could be well dispersed in 3,4-dihydroxyphenylpropionic acid modified chitosan-carboxymethylated β-cyclodextrin modified gelatin (CG) hydrogel due to the presence of DA, which endowed CG/DA-Ppy hydrogel with good adhesion properties, and the hydrogel adhered to the pigskin would not be dislodged by washing with running water. Under NIR, the CG/DA-Ppy hydrogel showed significant antimicrobial properties. Moreover, the CG/DA-Ppy hydrogel had excellent biocompatibility. In addition, CG/DA-Ppy hydrogel was effective in scavenging ROS, inducing macrophage polarization towards the M2 phenotype, and modulating the level of wound inflammation in vitro. Finally, it was confirmed in rat-infected wounds that the tissue regeneration effect and collagen deposition in the CG/DA-Ppy + NIR group were significantly better than the other groups in the repair of infected wounds, indicating better repair of infected wounds. The results suggested that the photothermal, antioxidant DA-Ppy conductive nanofiber had great potential for application in infected wound healing.

Degradation of STIM1 through FAM134B-mediated ER-phagy is potentially involved in cell proliferation

Autophagy is classified as non-selective or selective depending on the types of degrading substrates. Endoplasmic reticulum (ER)-phagy is a form of selective autophagy for transporting the ER-resident proteins to autolysosomes. FAM134B, a member of the family with sequence similarity 134, is a well-known ER-phagy receptor. Dysfunction of FAM134B results in several diseases including viral infection, inflammation, neurodegenerative disorder and cancer, indicating that FAM134B has crucial roles in various kinds of intracellular functions. However, how FAM134B-mediated ER-phagy regulates intracellular functions is not well understood. In this study, we found that FAM134B knockdown in mammalian cells accelerated cell proliferation. FAM134B knockdown increased the protein amount of STIM1, an ER Ca2+ sensor protein mediating the store-operated Ca2+ entry (SOCE) involved in G1 to S phase transition. FAM134B bound to STIM1 through its C-terminal cytosolic region. FAM134B knockdown reduced transport of STIM1 from the ER to autolysosomes. Finally, FAM134B knockdown accelerated G1 to S phase transition. These results suggest that FAM134B is involved in cell proliferation possibly through degradation of STIM1 via ER-phagy.

Promising anti-inflammatory activity of a novel designed anti-microbial peptide for wound healing

Chronic wounds can develop as a result of prolonged inflammation during the healing process, which can happen due to bacterial infection. Therefore, preventing infection and controlling inflammation can accelerate wound healing. Antimicrobial peptides have different protective properties in addition to antimicrobial activity. Some of these activities include the stimulation of cytokine or chemokine synthesis, the facilitation of chemotaxis and cell proliferation, the acceleration of cell proliferation, the induction of anti-inflammatory responses, and the promotion of wound repair. This study aimed to assess the wound healing potential of a novel in silico-designed antimicrobial peptide. Then, its anti-inflammatory activity was investigated by measuring the level of tumor necrosis factor-α (TNF-α) and transforming growth factor beta (TGF-β) as indicators of the wound healing process. In addition, the influence of the peptide on cell migration was evaluated by a scratch test on human dermal fibroblasts (HDF) and HaCaT cells as a human epidermal keratinocyte cell line. The results showed that our new peptide could act well in inhibiting TNF-α over-secretion while increasing the expression of TGF-β as an anti-inflammatory factor. This peptide showed a significant potential to stimulate HDF and HaCaT cell migration and proliferation. Therefore, using this peptide as an anti-inflammatory component of wound dressings may be promising.

Therapeutic effects of tetrahedral framework nucleic acids and tFNAs-miR22 on retinal ischemia/reperfusion injury.

Retinal ischemia/reperfusion injury (RI/R) is a common pathological process in ophthalmic diseases, which can cause severe visual impairment. The mechanisms underlying RI/R damage and repair are still unclear. Scholars are actively exploring effective intervention strategies to restore impaired visual function. With the development of nucleic acid nanomaterials, tetrahedral framework nucleic acids (tFNAs) have shown promising therapeutic potential in various fields such as stem cells, biosensors, and tumour treatment due to their excellent biological properties. Besides, miRNA-22-3p (miR-22), as an important regulatory factor in neural tissue, has been proven to have positive effects in various neurodegenerative diseases. By stably constructing a complex of tetrahedral framework nucleic acids miR22 (tFNAs-miR22), we observed that tFNAs-miR22 had a positive effect on the repair of RI/R injury in retinal neural tissue. Previous studies have shown that tFNAs can effectively deliver miR-22 into damaged retinal neurons, subsequently exerting neuroprotective effects. Interestingly, we found that there was a certain synergistic effect between tFNAs and miR-22. tFNAs-miR22 can selectively activated the ERK1/2 signalling pathway to reduce neuronal apoptosis, accelerate cell proliferation, and restore synaptic functional activity. In this study, we established a simple yet effective small molecule drug for RI/R treatment which may become a promising neuroprotectant for treating this type of vision impairment disease in the future.

Role of AMIGO2 in cancer progression: Novel insights (Review).

Adhesion molecule with IgG-like domain 2 (AMIGO2) is a novel scaffold protein initially identified in cerebellar granule neurons, and inhibits apoptosis of neurons. It is also widely expressed in various malignant tumors, including gastric cancer, colorectal carcinoma, ovarian cancer, prostate cancer and melanoma. During the past decades, it has been revealed that AMIGO2 can act as an oncogene, participating in tumor occurrence and development, for example by inhibiting apoptosis, accelerating cell proliferation, migration and adhesion, and promoting tumor metastasis and drug resistance. The present review discusses the recent advancements regarding AMIGO2 in the field of cancer, emphasizing its related molecular mechanisms to identify novel therapeutic strategies targeting AMIGO2 for cancer treatment in the future.

Low intensity mechanical signals promote proliferation in a cell-specific manner: Tailoring a non-drug strategy to enhance biomanufacturing yields

Biomanufacturing relies on living cells to produce biotechnology-based therapeutics, tissue engineering constructs, vaccines, and a vast range of agricultural and industrial products. With the escalating demand for these bio-based products, any process that could improve yields and shorten outcome timelines by accelerating cell proliferation would have a significant impact across the discipline. While these goals are primarily achieved using biological or chemical strategies, harnessing cell mechanosensitivity represents a promising – albeit less studied – physical pathway to promote bioprocessing endpoints, yet identifying which mechanical parameters influence cell activities has remained elusive. We tested the hypothesis that mechanical signals, delivered non-invasively using low-intensity vibration (LIV; <1 ​g, 10–500 ​Hz), will enhance cell expansion, and determined that any unique signal configuration was not equally influential across a range of cell types. Varying frequency, intensity, duration, refractory period, and daily doses of LIV increased proliferation in Chinese Hamster Ovary (CHO)-adherent cells (+79% in 96 ​hr) using a particular set of LIV parameters (0.2 ​g, 500 ​Hz, 3 ​× ​30 ​min/d, 2 ​hr refractory period), yet this same mechanical input suppressed proliferation in CHO-suspension cells (−13%). Another set of LIV parameters (30 ​Hz, 0.7 ​g, 2 ​× ​60 ​min/d, 2 ​hr refractory period) however, were able to increase the proliferation of CHO-suspension cells by 210% and T-cells by 20.3%. Importantly, we also reported that T-cell response to LIV was in-part dependent upon AKT phosphorylation, as inhibiting AKT phosphorylation reduced the proliferative effect of LIV by over 60%, suggesting that suspension cells utilize mechanism(s) similar to adherent cells to sense specific LIV signals. Particle image velocimetry combined with finite element modeling showed high transmissibility of these signals across fluids (>90%), and LIV effectively scaled up to T75 flasks. Ultimately, when LIV is tailored to the target cell population, it's highly efficient transmission across media represents a means to non-invasively augment biomanufacturing endpoints for both adherent and suspended cells, and holds immediate applications, ranging from small-scale, patient-specific personalized medicine to large-scale commercial bio-centric production challenges.

Diabetes Driven Oncogenesis and Anticancer Potential of Repurposed Antidiabetic Drug: A Systemic Review.

Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million reported cancer-related deaths in 2020. This review explores the pathological association between diabetes and diverse cancer progressions, examining molecular mechanisms and potential therapeutic intersections. From altered metabolic landscapes to dysregulated signaling pathways, the intricate links are delineated, offering a comprehensive understanding of diabetes as a modulator of tumorigenesis. Cancer cells develop drug resistance through mechanisms like enhanced drug efflux, genetic mutations, and altered drug metabolism, allowing them to survive despite chemotherapeutic agent. Glucose emerges as a pivotal player in diabetes progression, and serving as a crucial energy source for cancer cells, supporting their biosynthetic needs and adaptation to diverse microenvironments. Glycation, a non-enzymatic process that produces advanced glycation end products (AGEs), has been linked to the etiology of cancer and has been shown in a number of tumor forms, such as leiomyosarcomas, adenocarcinomas, and squamous cell carcinomas. Furthermore, in aggressive and metastatic breast cancer, the receptor for AGEs (RAGE) is increased, which may increase the malignancy of the tumor. Reprogramming glucose metabolism manifests as hallmark cancer features, including accelerated cell proliferation, angiogenesis, metastasis, and evasion of apoptosis. This manuscript encapsulates the dual narrative of diabetes as a driver of cancer progression and the potential of repurposed antidiabetic drugs as formidable countermeasures. The amalgamation of mechanistic understanding and clinical trial outcomes establishes a robust foundation for further translational research and therapeutic advancements in the dynamic intersection of diabetes and cancer.

Zirconium ion mediated collagen nanofibrous hydrogels with high mechanical strength

Low mechanical strength is still the key question for collagen hydrogel consisting of nanofibrils as hard tissue repair scaffolds with no loss of biological function. In this work, novel collagen nanofibrous hydrogels with high mechanical strength were fabricated based on the pre-protection of trisodium citrate masked Zr(SO4)2 solution for collagen self-assembling nanofibrils and then further coordination with Zr(SO4)2 solution. The mature collagen nanofibrils with d-period were observed in Zr(IV) mediated collagen hydrogels by AFM when the Zr(IV) concentration was ≥ 10 mmol/L, and the distribution of zirconium element was uniform. Due to the coordination of Zr(IV) with ─COOH, ─NH2 and ─OH within collagen and the tighter entanglement of collagen nanofibrils, the elastic modulus and compressive strength of Zr(IV) mediated collagen nanofibrous hydrogel were 208.3 and 1103.0 kPa, which were approximate 77 and 12 times larger than those of pure collagen hydrogel, respectively. Moreover, the environmental stability such as thermostability, swelling ability and biodegradability got outstanding improvements and could be regulated by Zr(IV) concentration. Most importantly, the resultant hydrogel showed excellent biocompatibility and even accelerated cell proliferation.

Abstract PO-019: Ubiquitin E3 ligase OSTM1 regulates the cAMP/PKA/CREB pathway and suppresses B-cell malignancies

Abstract B-cell malignancies (BCM) often arise from genomic alterations introduced during different stages of B-cell development. Here, we performed a whole genome targeting CRISPR/Cas9 screen in the immortalized yet non-transformed IL-3-dependent Ba/F3 murine pro-B cell line to identify genes whose loss confers IL-3 independence, reasoning that these genes may function as tumor suppressor genes (TSGs) in BCM. One of the candidate genes is osteoporosis-associated transmembrane protein 1 (OSTM1), an E3 ubiquitin ligase whose loss-of-function causes autosomal recessive osteoporosis. Informatics analysis of patient data showed that OSTM1 is frequently deleted across BCM, which co-occurs with the deletion of a well-characterized TSG Cdkn2a. Genetic silencing of OSTM1 in Ba/F3 cells conferred IL-3-independent survival and proliferation, as well as splenomegaly, lymphadenopathy, and abnormal peripheral blood cell count, indicative of transformation in vivo. Using mass spectrometry screens, we identified phosphodiesterase 3B (PDE3B) as an interacting partner of OSTM1. OSTM1 ubiquitylates PDE3B and promotes its proteasomal degradation. The OSTM1-PDE3B interaction and PDE3B degradation are negatively regulated by OSTM1 N-glycosylation. As PDE3B catalyzes the conversion of cAMP to AMP, it negatively regulates the cAMP-dependent PKA/CREB/CREBBP tumor suppressive pathway. Indeed, overexpression of PDE3B accelerated cell proliferation while PDE3B silencing in OSTM1 KO cells reversed the transformation phenotype in cell lines and in mouse allograft tumors. Importantly, a strong correlation between OSTM1 disruption, increased PDE3B stability, and decreased PKA/CREB/CEBBP signaling was observed in cell lines and in BCM patient datasets. Finally, CD19-Cre mediated B-cell specific ablation of OSTM1 cooperated with CDKN2A deletion to drive spontaneous immature B-cell lymphomagenesis in mice. Collectively, these results indicate that OSTM1 is a novel TSG which targets PDE3B for proteasomal degradation. Loss of OSTM1 enhances PDE3B stability and abrogates the tumor-suppressive role of cAMP/CREB/CREBBP pathway which promotes BCM. Citation Format: Muhammad Usama Tariq, Julia Shen, Jaeyong Jung, Namratha Sheshadri, Junrong Yan, Rongrong Li, Kevin Lu, Tong Liu, Hong Li, Yue Lynn Wang, Ping Xie, Wei-Xing Zong. Ubiquitin E3 ligase OSTM1 regulates the cAMP/PKA/CREB pathway and suppresses B-cell malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-019.

Long intergenic non-protein coding RNA 1436 accelerates cell proliferation, migration and adhesion properties of the MUM-2B cell line via microRNA-513a-5p/CUG Triplet repeat-binding protein 1 axis to activate the phosphatidylinositol 3-kinase/Akt signaling pathway

Long intergenic non-protein coding RNA 1436 accelerates cell proliferation, migration and adhesion properties of the MUM-2B cell line via microRNA-513a-5p/CUG Triplet repeat-binding protein 1 axis to activate the phosphatidylinositol 3-kinase/Akt signaling pathway

EEF1D stabilized by SRSF9 promotes colorectal cancer via enhancing the proliferation and metastasis.

Colorectal cancer (CRC) is the third most common cancer and causes high mortality worldwide. Although CRC has been studied widely, the molecular mechanism is not completely known. Eukaryotic translation elongation factor 1 delta (EEF1D) participates in the progression of various tumors, however, the effect of EEF1D on CRC remains unclear. Here, we aimed to identify the potential mechanism of EEF1D in CRC. The expression levels of EEF1D were assessed in CRC samples. Functional analysis of EEF1D in CRC was detected in vitro and in vivo. The regulatory mechanism of EEF1D was identified with RNA immunoprecipitation, RNA pull-down assay, and proteomics analysis. Our findings confirmed that EEF1D was upregulated in human CRC tissues. Functionally, EEF1D overexpression accelerated cell proliferation and metastasis, whereas EEF1D knockdown inhibited cell proliferation and metastasis both in vitro and in vivo CRC models. Furthermore, we showed that EEF1D was upregulated by SRSF9 via binding to 3'UTR of EEF1D mRNA. EEF1D knockdown reversed the malignant phenotype induced by SRSF9 overexpression. These findings demonstrated that EEF1D promotes CRC progression, and EEF1D may be a molecular target against CRC.