Cancer Cell Proliferation Research Articles

Prediction of Secondary Metabolite Compounds in Lotus (Nelumbo nucifera Gaertn.) Targeting Androgen-α Receptors for Breast Cancer Treatment Using Molecular Docking

Breast cancer (BC) is a malignant tumor that grows in the breast tissue and can spread to other organs. BC is often found at an advanced stage and therefore has a poor prognosis. With 68,858 cases, BC is the most common type of cancer in Indonesia. The development of breast carcinoma is strongly influenced by steroid hormones and their receptors, such as estrogen, progesterone, and androgen. Androgen receptors (AR) are found more (70-90%) compared to estrogen receptors (60-80%) and progesterone receptors (50-70%). Therefore, research on natural compounds that inhibit cancer cell proliferation influenced by AR needs to be increased. The lotus plant (Nelumbo nucifera Gaertn.) has been used as a traditional herbal medicine and food in Asia. Bioactive compounds in lotus have therapeutic potential against BC. In the pharmacophore screening results, five hit compounds were found: isorhamnetin, luteolin, catechin, kaempferol, and apigenin. The compound with the best pharmacophore fit score value is isorhamnetin with a value of 41.31, while the compound with the best binding affinity to AR is kaempferol with a binding affinity of -9.44 and an inhibitor constant of 121.12 nM.Keywords: breast-cancer, androgen-α receptor, lotus, molecular docking.

Probiotic-Derived Metabolites from Lactiplantibacillus plantarum OC01 Reprogram Tumor-Associated Macrophages to an Inflammatory Anti-Tumoral Phenotype: Impact on Colorectal Cancer Cell Proliferation and Migration

Background: Tumor-associated macrophages (TAMs) are key players in the colorectal cancer (CRC) tumor microenvironment (TME), representing the most abundant immune cells within it. The interplay between the intestinal microbiota, macrophages, and cancer cells significantly impacts tumor progression by driving macrophage polarization. Particularly, the polarization into the pro-tumoral M2-like TAM phenotype promotes the extracellular matrix remodeling, cancer cell proliferation, metastasis, immune suppression, and therapy resistance. Probiotic metabolites can disrupt this crosstalk, possibly reverting the TAM polarization toward a pro-inflammatory anti-tumoral phenotype, thus potentially benefiting the intestinal mucosa and opposing CRC progression. Previously, we showed that Lactiplantibacillus plantarum OC01 metabolites counter interleukin (IL)-6-induced CRC proliferation and migration. Methods: Here, we explore how probiotics affect CRC secretome and how this influences TAM polarization, which then impacts CRC malignancy. Results: The conditioning medium (CM) from CRC cells indeed promoted the polarization of macrophage toward the M2-like phenotype, whereas the CM from CRC pre-treated with L. plantarum OC01 metabolites induced a pro-inflammatory macrophage phenotype, characterized by NLRP3 inflammasome activation and reactive oxygen species (ROS) production, and by decreased expression of the M2 phenotype markers CD206 and CD163. Consistently, the expression of tumor growth factor (TGF)-β, a promoter of M2 macrophage polarization, was reduced in CRC cells treated with L. plantarum OC01. The pro-inflammatory macrophages inhibited CRC proliferation and migration. Conclusions: Overall, our study highlights the potential of metabolites from L. plantarum OC01 to reprogram the metabolism in cancer cells and thus reshape the TME by shifting TAMs toward a more inflammatory and anti-tumoral phenotype, emphasizing the promise of probiotics in advancing novel therapeutic approaches for CRC.

CircMETTL6 Suppresses Ovarian Cancer Cell Growth and Metastasis Through Inhibition of GDF15 Transcription by Disrupting the NONO-POLR2A Complex.

Circular RNAs (circRNAs) are a distinctive class of non-coding RNAs with covalent closed-loop structure, lacking 5' caps and 3' poly(A) tails. These molecules are prevalent in eukaryotes and play keyroles in cancer. Here, the function of a new circRNA, circMETTL6, in ovarian cancer is identified and investigated. The prognostic significance of circMETTL6 is assessed using RNA in situ hybridization. Functional studies involving circMETTL6 overexpression are performed both in vitro and in vivo. Mechanistic investigations are performed using RNA-seq, RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, protein degradation assay and dual-luciferase reporter assays. circMETTL6 is significantly downregulated in ovarian cancer, and its lower expression correlates with worse prognosis. Overexpression of circMETTL6 significantly inhibited proliferation, migration, and invasion of ovarian cancer cell in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, circMETTL6 recruited the non-POU domain containing octamer binding protein (NONO) by binding to its Coiled-coil domain and disrupted its binding with RNA polymerase II subunit A (POLR2A), and consequently inhibiting growth differentiation factor 15 (GDF15) transcription, thereby suppressing ovarian cancer progression. These findings establish circMETTL6 as a novel tumor suppressor in ovarian cancer. Targeting the circMETTL6/NONO/GDF15 axis presents a potential therapeutic avenue for ovarian cancer treatment.

Targeting the hERG1/β1 integrin complex in lipid rafts potentiates statins anti-cancer activity in pancreatic cancer

Plasma membrane macromolecular complexes function as signaling hubs that regulate cell behavior, which is particularly relevant in cancer. Our study provides evidence that the complex formed by the hERG1 potassium channel and the β1 subunit of integrin receptors preferentially localizes in Lipid Rafts (LRs) in Pancreatic Ductal Adenocarcinoma (PDAC) cell lines and primary samples. The complex recruits the p85 subunit of phosphatidyl-inositol-3-kinase (PI3K), activating phosphoinositide metabolism and triggering an intracellular signaling pathway centered on Akt. This pathway ultimately affects cancer cell proliferation through cyclins and p21, and cell migration through the small GTPase Rac-1 and f-actin organization. The hERG1/β1 integrin complex in LRs can be dissociated and the downstream signaling pathway can be inhibited by either disrupting LRs through methyl-beta-cyclodextrin (MβCD) or inhibiting cholesterol synthesis by statins. Treatment with a single chain bispecific antibody—scDb-hERG1-β1—specifically targeting the complex significantly potentiates the effects of both MβCD and statins on intracellular signaling. Consequently, these treatments decrease PDAC cell proliferation and motility in vitro. From a pharmacological perspective, different statins produce anti-neoplastic effects in synergy with scDb-hERG1-β1. Such combination also enhances tumor sensitivity to chemotherapeutic drugs, such as gemcitabine and oxaliplatin. The efficacy of these combination treatments depends on the amount of the hERG1/β1 integrin complex present on the plasma membrane of cancer cells. Finally, the combined treatment with statins and scDb-hERG1-β1 significantly reduces tumor growth and improves survival in vivo, in a preclinical mouse model. These results suggest that the combination of scDb-hERG1-β1 and statins represent a potential novel strategy for treating PDAC patients.

Studying the impact of chitosan salicylaldehyde/schiff base/CuFe2O4 in PC3 cells via theoretical studies and inhibition of PI3K/AKT/mTOR signalling

In this elucidation, the nucleophilic attack of salicyladehyde with chitosan, which was obtained from the shrimp shell, afforded the cellulose aldehyde (Schiff base), and then the dispersion of CuFe2O4 on the surface of cellulose aldehyde gave the novel nanomaterial of bimetallic oxide, which was confirmed through spectral analysis such as FT-IR, NMR, SEM, and XRD analysis. Moreover, the anti-proliferative effect of chitosan, chitosan salicylaldehyde, and chitosan salicylaldehyde/CuFe2O4 was evaluated in PC3 human prostate cancer cells and HSF normal human skin fibroblasts. After 48 h, PC3 cell proliferation was significantly inhibited by chitosan salicylaldehyde/CuFe2O4 and chitosan salicylaldehyde (IC50 = 35.3 and 45.55 µg/ml, respectively) without any effects on normal HSF cells. The mRNA expression levels of PI3K, AKT, mTOR, and CCND1 were examined in PC3-treated cells by using QRT-PCR, and the results demonstrated that, by down-regulating the expression levels of these genes, chitosan salicylaldehyde/CuFe2O4 significantly affected prostate cancer cell proliferation, progression, and autophagy more than chitosan salicylaldehyde. Furthermore, the docking stimulation of the chitosan derivatives with different proteins showed the presence of CuFe2O4 particles effect on the interaction inside their pockets and increased the activities, and it’s related to biological evaluation. Additionally, the theoretical investigation of these chitosan derivatives and the determination of their physical descriptors showed the activity of bimetallic oxide and the presence of electrostatic hydrogen bond interaction. Finally, these findings may suggest that chitosan salicylaldehyde/CuFe2O4 has a promising anticancer impact against prostate cancer.

Nimbolide attenuates hepatocellular carcinoma by regulating miRNAs 21, 145 and 221 and their target gene expression.

MicroRNAs (miRNAs) are becoming progressively emerging in cancer research from an etiologic and curative point of view. Several miRNAs act as oncogenes or tumor suppressors, which are dysregulated in numerous cancers. Our previous studies have established that nimbolide (a bioactive terpenoid from neem) attenuated hepatocellular carcinoma (HCC) through various mechanisms in mice. Here, we aimed to elucidate the effect of nimbolide in modulating specific miRNAs (21, 145, and 221) and their target genes involved in promoting inflammation and cancer cell proliferation in HCC mice. Following the induction of HCC in mice at 28weeks, nimbolide (6mg/kg b.wt.) was administered orally for four consecutive weeks. We found significantly increased hepatic expression of miR-21a-3p, miR-21a-5p, miR-221-5p and miR-221-3p whilst significantly decreased miR-145a-5p in HCC mice. Nimbolide treatment to HCC mice substantially reduced the miR-21a-5p and miR-221-3p and improved miR-145a-5p gene expression. Our in-silico study also supports these findings. Moreover, hepatic tight junction (TJ) associated proteins such as claudins 1&5 mRNA and protein were increased considerably, whilst significantly decreased hepatic claudin 2 mRNA and protein expression noted in HCC mice. Nimbolide also regulates cadherins, ROCK 1, MMP 9, cyclin D1, CDK4, NF κB and TNFα mRNA expression in HCC mice. We identified for the first time that nibmolide treatment to HCC mice significantly attenuated hepatic miRNAs 21 & 221 expressions and sheltered miR-145 expression. These findings were further confirmed with in-silico studies. Moreover, nibmolide treatment in HCC mice regulates miRNA target genes involved in cancer cell proliferation and inflammation, thereby attenuating HCC progression in mice.

Activity-Regulated Cytoskeleton-Associated Protein Gene Expression Is Associated With High Infiltration of Stromal Cells and Immune Cells, but With Less Cancer Cell Proliferation and Better Overall Survival in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancers.

Peritumoral lidocaine infiltration prior to excision is associated with better survival in breast cancer (BC), which led us to hypothesize that innervation to the tumor affects its biology and patient survival. Activity-regulated cytoskeleton-associated protein (ARC) gene expression is known to be regulated by neuronal activity. Therefore, we studied the clinical relevance of ARC gene expression as a surrogate of neuronal activity in BC. Sweden Cancerome Analysis Network - Breast (SCAN-B (GSE96058), n = 3,273) cohort and The Cancer Genome Atlas (TCGA, n = 1,069) were analyzed. High ARC expression was significantly associated with smaller tumor size, without lymph node metastasis, and less stage IV disease in one cohort, but not validated by the other. Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) and luminal A expressed significantly higher ARC compared to the other subtypes in both cohorts (P < 0.005). High ARC BC was significantly associated with lower Nottingham histological grade and lower Ki67 gene expression consistently in ER+/HER2- but not triple negative breast cancer (TNBC) in both cohorts (P < 0.001). Cell proliferation-related gene sets in the Hallmark collection (E2F targets, G2M checkpoint, and mitotic spindle) were significantly enriched to low ARC BC in ER+/HER2- but not TNBC in TCGA. The stromal cells (fibroblasts, vascular endothelial cells, and adipocytes) were all significantly infiltrated in high ARC ER+/HER2-, but not in TNBC, except for neurons. Homologous recombination deficiency, intratumor heterogeneity, fraction altered, silent or non-silent mutation rate were all significantly lower in high ARC ER+/HER2- but not TNBC. Although there was no difference in single nucleotide variant or indel neoantigens, tumor infiltrating lymphocytes, and cytolytic activity by ARC expression regardless of subtype, multiple immune cells were significantly infiltrated in high ARC ER+/HER2-, including CD8, CD4 memory cells, helper type II T cells, regulatory T cells, M2 macrophages, and B cells (all P < 0.03 in both cohorts), but not in TNBC. Disease-specific and overall survival were significantly improved in high ARC ER+/HER2- consistently in both cohorts (all P < 0.05), but this was not the case in TNBC. ARC gene expression was associated with less cancer cell proliferation, high infiltration of stromal cells and immune cells, and better survival in the ER+/HER2- but not TNBC subtype.

Effect of tRF-28-ZJ47D112Z4DZ on the pathogenesis of gastric cancer through targeting cyclin D1/CDK4 and its early diagnostic value.

475 Background: Gastric cancer exhibits high incidence and mortality rates worldwide. Current research on gastric cancer aims to discover stable and effective early diagnostic markers, as well as uncover the disease's pathogenesis. tRNA-derived fragment (tRF) is a newly discovered regulatory non-coding RNA, which plays an important role in tumor diagnosis and treatment. Methods: This study, through transcriptome sequencing and MINTBase v2.0 database, screened out a new molecule tRF-28-ZJ47D112Z4DZ (tRF-28) related to gastric cancer. An absolute quantitative method was established to quantify the level of tRF-28 in plasma. ROC curve, survival curve, Cox regression model were constructed, and clinicopathological factors were collected to analyze the diagnostic value of tRF-28. "Overexpression" and "knockdown" tRF-28 gastric cancer cell models and xenograft tumor models were established to study the effects of tRF-28 on cell proliferation. Using bioinformatics, qRT-PCR, Western blot, dual luciferase reporter gene, fluorescence in situ hybridization, RNA binding protein immunoprecipitation assay, rescue experiment and immunohistochemistry to study the regulatory role of tRF-28 by binding to the 3'UTR of CCND1. Results: This study clarified the tRF-28 levels in the plasma of healthy individuals, and gastric benign and malignant lesions, providing a new candidate biomarker for the early diagnosis of gastric cancer. Through upregulating and downregulating the level of tRF-28 in gastric cancer cells, it was revealed that tRF-28 inhibits the proliferation of gastric cancer cells in vivo and in vitro by regulating key proteins such as Cyclin D1, CDK4, Rb, and p-Rb. In studying specific molecular mechanisms, tRF-28 and CCND1 were co-located in the cytoplasm. tRF-28 combines with Ago2 protein to form a complex and plays a role in silencing the target gene CCND1 in the cytoplasm. The rescue experiments revealed that silencing the target gene CCND1 can reverse the carcinogenesis effect of tRF-28 inhibitors, clarifying the biological functions of tRF-28 by regulating CCND1. Conclusions: Based on a series of research findings, we elucidated that tRF-28 form a complex with Ago2 protein, binding to the 3' UTR of CCND1 to downregulate Cyclin D1, CDK4, and other critical proteins, thereby inhibiting the proliferation of gastric cancer cells. Our study aims to offer new insights into identifying potential early diagnostic markers and therapeutic targets for gastric cancer.

Circular RNA circPFKP suppress gastric cancer progression through targeting miR-346/CAMD3 axis.

Studies have demonstrated that circular RNAs (circRNAs) exert an important regulatory function in the pathogenesis of various tumors. However, their role in gastric cancer (GC) is still not completely understood. In our study, the differentially expressed circRNAs in GC tissues and matched adjacent normal tissues were analyzed by utilizing gene chips GSE93541, GSE89143, and GSE78092. The expression of has_circ_0006608 (circPFKP), miR-346, and CAMD3 was analyzed through quantitative real-time polymerase chain reaction (qRT-PCR). The CCK-8 assay and Transwell assay were employed to detect the effect of circPFKP on the proliferation, migration, and invasion of gastric cancer cells. The mice xenograft assay was used to assess the function of circPFKP in vivo. The targeting relationship between circPFKP, miR-346, and CAMD3 was predicted by bioinformatics analysis and confirmed by the dual-luciferase reporter assay and RNA pull-down assay. Our results screened and verified that circPFKP was down-regulated in gastric cancer tissues and cells. Overexpression of circPFKP in GC cells can inhibit cell proliferation, migration, invasion, and tumor growth in vivo. Additionally, circPFKP has been shown to act as a sponge for miR-346 to modulate the expression of CAMD3. Finally, we demonstrated that overexpression of CAMD3 or miR-346 inhibitor significantly reversed the effects of si-circPFKP on the proliferation, migration, and invasion of gastric cancer cells. In conclusion, this study provided that circPFKP inhibits the progression of GC via the miR-346/CAMD3 axis, this may provide a noval biomarker for the diagnosis and treatment of GC.

Influence of the ERK/CHGB pathway in breast cancer progression under chronic stress.

Breast cancer is one of the most common malignancies among women, and its development involves a variety of complex molecular mechanisms. Extracellular signal-regulated kinase (ERK) and Chromogranin B (CHGB) are known to play key roles in various cancers. This study aims to explore the impact of the ERK/CHGB pathway in a chronic stress environment simulated by salbutamol on the development of breast cancer. This study utilized female BALB/c mice to establish a breast cancer model, dividing them into control, salbutamol-treated, and salbutamol-inhibitor-treated groups. Cell culture, immunohistochemistry, Western Blot, real-time fluorescent quantitative PCR, and Transwell migration assays were employed to assess the effects of salbutamol and the ERK/CHGB pathway. Salbutamol treatment significantly enhanced the proliferation, migration, and invasiveness of breast cancer cells, associated with the activation of the ERK pathway and the inhibition of CHGB. The salbutamol-inhibitor-treated group exhibited a marked suppression of these effects. Additionally, the interaction of the ERK/CHGB pathway in an extracellular stress environment provided advantages for the survival and proliferation of breast cancer cells. This study demonstrates that a chronic stress environment simulated by salbutamol can promote malignant behaviors in breast cancer cells through the ERK/CHGB pathway. These findings offer new molecular targets for breast cancer treatment and highlight the potential importance of managing chronic stress and blocking specific molecular pathways in cancer therapy.

The mechanism study of LncRNA AC012181.2 targeting HERPUD1 protein in regulating stromal stem cells participating in metabolic reprogramming for gastric cancer metastasis.

To investigate the role of long non-coding RNAs (lncRNAs) in the metabolic reprogramming of gastric cancer through their regulation of mesenchymal stem cells (MSCs) and HERPUD1 protein targets, aiming to elucidate mechanisms that could lead to novel therapeutic strategies. The RNA-seq was performed on BGC and hMSC-BGC cells to perform LncRNA screening. And we employed cell culture techniques using hMSC-BM and BGC823 cells, treated with various genetic interventions including siRNA and overexpression vectors. Techniques such as cell viability assays, quantitative PCR (qPCR), Western blotting, RNA pull-down and RNA-FISH were utilized to validate the interaction between lncRNA AC012181.2 and HERPUD1 protein. Flow cytometry were utilized to analyze the impacts of lncRNA AC012181.2 on gene and protein expression related to cancer metabolism. Additionally, a tumorigenic model in nude mice was used to observe the in vivo effects. Modulation of AC012181.2 in MSCs significantly affected the proliferation, migration, and invasion capabilities of BGC823 gastric cancer cells. Knockdown of AC012181.2 resulted in reduced tumor growth in mouse models, along with changes in key gene and protein expression levels associated with cancer metabolism. Overexpression of AC012181.2 showed the opposite effect, enhancing tumor growth and altering cellular behaviors and molecular expressions in favor of cancer progression. The lncRNA AC012181.2 is crucial for gastric cancer metabolic reprogramming by regulating HERPUD1 Protein. Targeting it offers a promising avenue to impact the tumor microenvironment and develop novel gastric cancer therapies.

GTPase GPN3 facilitates cell proliferation and migration in non-small cell lung cancer by impeding clathrin-mediated endocytosis of EGFR

Small GTPases play a critical role as regulatory molecules in signaling transduction and various cellular processes, contributing to the development of human diseases, including cancers. GPN3, an evolutionarily conserved member of the GPN-loop GTPase subfamily classified in 2007 according to its structure, has limited knowledge regarding its cellular functions and molecular mechanisms. In this study, we demonstrate that GPN3 interacts with clathrin light chain A (CLTA), a vesicle coat protein, as well as clathrin-mediated endocytosis associated modulators AP2B1 and AP2S1. Upregulation of GPN3 leads to the inhibition of clathrin-coated pit invagination. Furthermore, we discovered that GPN3 interacts with the epidermal growth factor receptor (EGFR) and regulates the co-localization of EGFR and CLTA, as well as the localization of EGFR in early endosomes upon EGF stimulation. As a result, this leads to a decrease in endocytic levels of EGFR and an increase in the accumulation of EGFR on the cell membrane surface, thereby prolonging activation of EGFR signaling. The functional effects exerted by GPN3 are dependent on cellular levels of GTP abundance. Furthermore, our findings indicate that aberrant overexpression of GPN3 is observed in non-small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues, and high expression levels of GPN3 are associated with poor prognosis for NSCLC patients. Collectively, these findings reveal that GPN3 acts as an oncogene promoting cell proliferation and migration in NSCLC through regulation of clathrin-dependent EGFR endocytosis. These results suggest that targeting GPN3 could serve as a novel prognostic biomarker and therapeutic strategy for NSCLC treatment.

Cross-Talk between NOK and EGFR: Juxtamembrane and Kinase domain interactions enhancing STAT3/5 signaling in breast cancer tumorigenesis.

Epidermal growth factor receptor (EGFR) plays an important role in the regulation of cell proliferation and migration [1]. It forms a homodimer or heterodimer with other ErbB receptor family members to activate downstream signaling. Emerging evidence indicates that the EGFR activity and downstream signaling are regulated by other proteins except its family members during tumorigenesis. Hence, investigating the diverse partnership profiles of EGFR is crucial for elucidating the mechanisms underlying EGFR-mediated actions in tumors, which in turn can guide the development of targeted therapeutic strategies. Here we report that NOK (also known as STYK1), a novel tyrosine kinase cross-talks with EGFR to promote tumorigenesis and metastasis of breast cancer cells. We found that NOK directly interacted with EGFR and formed a heterodimer complex in a manner of cross interaction via their juxtamembrane (JM) domains and kinase domains. Depletion of NOK impaired, but over-expression of NOK increased, the phosphorylation of EGFR. NOK enhanced EGF-induced phosphorylation of STAT3 and STAT5 via its juxtamembrane (JM) domain in promoting the proliferation and migration of breast cancer cells. Overexpression of NOK and EGFR synergistically induced the tumorigenesis of NIH-3T3 normal cells. We demonstrated that co-expression of NOK and EGFR correlated with tumor malignant stages in breast cancer patients. Our finding introduces a new cross interaction manner of EGFR-NOK via juxtamembrane (JM) domains and kinase domains, uncovers a mechanism by which NOK coordinates EGFR to enhance EGF-STAT3/5 signaling during tumorigenesis and metastasis, and proposes a potential strategy for targeting NOK-EGFR in breast cancer treatment.

USP34 regulates PIN1-cGAS-STING axis-dependent ferroptosis in cervical cancer via SUMOylation.

Cervical cancer is a prevalent form of cancer in women, and the inhibition of ferroptosis has been shown to promote the progression of cervical cancer tumours. This study aimed to investigate the role of PIN1 in regulating ferroptosis in cervical cancer, focusing on its ability to modulate the cGAS-STING pathway and the potential involvement of USP34 as an upstream regulator of PIN1. PIN1-overexpressing and PIN1-knockdown cell lines were constructed. In addition to activating p-STING via PIN1 knockdown and inhibiting p-STING via PIN1 overexpression, cell activity was evaluated via CCK8, EdU, transwell and flow cytometry assays. The expression of USP34, PIN1, cGAS, p-STING, and STING was analysed through qRT-PCR and immunofluorescence. Western blot analysis was used to detect the regulatory effects of USP34, PIN1, cGAS, p-STING, and STING, as well as SUMOylation. Ferroptosis was detected by ROS immunofluorescence, the mitochondrial membrane potential, and mitochondrial electron microscopy. Furthermore, PIN1-knockdown cells were used to construct xenograft tumours in BALB/c male nude mice, and the relevant verification experiments were performed in vivo. PIN1 can increase the proliferation and invasion of cervical cancer cells by significantly inhibiting ferroptosis. The mechanism by which PIN1 promotes cancer is inhibition of the cGAS-STING pathway. Additionally, we found that USP34 could increase the expression of PIN1 via SUMOylation in cervical cancer cells. This study confirmed that USP34 could upregulate PIN1 expression and SUMOylation, thereby inhibiting ferroptosis by suppressing the cGAS-STING pathway and in turn promoting the progression of cervical cancer.

LncRNA TCONS_00251376 promotes the proliferation and migration of gastric cancer cell through upregulating ETV1.

Although there have been significant advancements in the treatment modalities for gastric cancer (GC) in recent years, the overall prognosis remains poor, particularly for individuals in advanced stages. The absence of a sensitive tumor marker in GC is a crucial factor contributing to this challenge. Our study focused on investigating a newly discovered long noncoding RNA (lncRNA) known as TCONS_00251376, which has been confirmed to exhibit differential expression in GC compared to adjacent tissues. To further validate these expression differences, we collected 22 pairs of GC and adjacent noncancerous tissues. Subsequent cell function experiments and animal studies were conducted to elucidate the role and underlying mechanisms of lncRNA TCONS_00251376 in the development of GC. The study revealed a significant upregulation of lncRNA TCONS_00251376 in cancer tissues (p < 0.01) and a consistent upregulation in GC cell lines (AGS, MKN45, BGC-823, and MGC-803). Furthermore, it was observed that lncRNA TCONS_00251376 played a promotive role in the proliferation, migration, and invasion of GC cells. Subsequent analysis indicated that lncRNA TCONS_00251376 could upregulate the expression of ETV1, a factor associated with the prognosis of GC. Therefore, our findings suggest that lncRNA TCONS_00251376 functions as an oncogenic lncRNA, promoting tumorigenesis and progression by regulating the expression of ETV1 gene. This highlights its potential as an effective target for treating GC.

ALKBH5 knockdown suppresses gastric cancer progression by reducing the expression of long non-coding RNA TUG1.

This study aimed to explore the relationship between m6A demethylase ALKBH5 and long noncoding RNA TUG1 (TUG1), as well as their effects on proliferation, migration, and angiogenesis in gastric cancer (GC) cells. The Cancer Genome Atlas (TCGA) database was utilized to analyze the relative expression levels of ALKBH5, TUG1, and vascular endothelial growth factor A (VEGFA). Survival analyses of TUG1, ALKBH5, and VEGFA were performed using the Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier databases. The binding sites of TUG1 and ALKBH5 were predicted using the Annolnc2 database. The correlation between ALKBH5 and TUG1 expression was analyzed using the GEPIA database. Subsequently, small interfering RNA (siRNA) targeting ALKBH5 and TUG1 was transfected into SGC-7901 cells, and functional studies were conducted using quantitative real-time polymerase chain reaction (qRT-PCR), CCK-8 assays, colony formation assays, transwell assays, and angiogenesis assays. Bioinformatics analysis indicated that ALKBH5, TUG1, and VEGFA were highly expressed in gastric cancer tissues and exhibited a positive correlation. Survival analysis revealed that high expression levels of ALKBH5, TUG1, and VEGFA were significantly associated with poor prognosis in gastric cancer patients. Binding sites for TUG1 and ALKBH5 were identified. Functional experiments demonstrated that the knockdown of ALKBH5 resulted in the downregulation of TUG1, which subsequently reduced the proliferation, invasion, migration, and angiogenesis of gastric cancer cells. The m6A demethylase ALKBH5 promotes gastric cancer progression by erasing the methylation modification of TUG1 and increasing TUG1 expression. This finding provides a new perspective for the treatment and prognosis assessment of gastric cancer.

The role of exosomal non-coding RNAs in the breast cancer tumor microenvironment.

The leading form of cancer affecting females globally is breast cancer, characterized by an unregulated growth of cells within the breast. Therefore, examining breast tissue is crucial in accurately identifying and treating this disease. Exosomes are very small enclosures bounded by a layer of cells and produced by a variety of cells present in the cancerous tissue surroundings. They play a crucial role in several biological functions in cancerous tumors. These exosomes carry non-coding RNAs (ncRNAs) and are discharged into the TME, where they are instrumental in the development and advancement of tumors. Additionally, the ncRNAs enclosed in exosomes act as significant mediators of communication within cells. Consequently, there is limited comprehension regarding the precise roles and targets of exosomal RNA in regulation, as research in this area is still in its preliminary phases. This piece provides a comprehensive overview of the latest studies on exosomes, delving into their impact on the behavior of cancer cells and immune cells. Moreover, it presents a compilation of the diverse forms of non-coding RNA molecules found in exosomes released by both cancerous and supportive cells, including circular RNAs, microRNAs, and long non-coding RNAs.Current research has proven the noteworthy influence that non-coding RNA molecules have on the progression, proliferation, drug resistance, and immune responses of breast cancer cells.

UGCG promotes chemoresistance and breast cancer progression via NF-κB and Wnt/β-catenin pathway activation.

Taxane-based chemotherapy is the primary treatment for triple-negative breast cancer (TNBC), yet clinical outcomes remain unsatisfactory due to the persistence of chemoresistance. Identifying key factors that contribute to chemoresistance and understanding the associated molecular mechanisms is therefore essential. The GEO databases were utilized to pinpoint factors related to chemoresistance, which were subsequently validated using clinical tissue samples. The role of UGCG in the malignant progression and chemoresistance of TNBC was assessed through various functional assays. Western blotting, qRT-PCR, and immunohistochemistry were employed to investigate the signaling pathways associated with UGCG in TNBC. UGCG expression was notably elevated in chemoresistant breast cancer tissues and cells, as identified in GEO databases and confirmed through immunohistochemistry. Additionally, findings from our cohorts indicated that higher levels of UGCG expression correlated with a lower rate of pathological complete response (pCR), suggesting it could serve as an independent predictor of chemotherapy effectiveness. Gain- and loss-of-function experiments demonstrated that UGCG enhanced the proliferation, metastasis, and stemness of breast cancer cells. Furthermore, treatment with paclitaxel or docetaxel resulted in increased UGCG expression, which in turn reduced chemotherapy-induced cell apoptosis and improved drug resistance and metastatic capabilities. Mechanistically, UGCG was found to amplify the activation of NF-κB and Wnt/β-catenin pathways, and the use of inhibitors targeting these pathways diminished the UGCG-induced malignant effects. Our findings underscore the significant role of UGCG in the chemoresistance and progression of breast cancer, suggesting it as a predictive biomarker and potential therapeutic target to combat chemoresistance in this disease.

Succinate supplementation alleviates liver cancer by inhibiting the FN1/SQLE axis-mediated cholesterol biosynthesis.

Succinate is a crucial metabolite in the TCA cycle and contributes to cancer development. However, the role of exogenous succinate in hepatocellular carcinoma (HCC) is unclear. Here, we report that the concentration of succinate in HCC tissues is lower compared to adjacent normal tissues, as determined by spatial metabolomics and quantitative metabolomics analysis. Succinate supplementation exhibits an anti-tumorigenic effect, inhibiting cell proliferation and colony formation in liver cancer cells but not in non-tumor LO2 cells. Additionally, succinate supplementation significantly reduces tumor formation in xenograft nude mice models and carcinogen-induced WT mice models. The anti-tumorigenic function of succinate is mechanistically mediated by FN1-activated SQLE-related cholesterol biosynthesis. Our study demonstrates that exogenous succinate acts as a cholesterol biosynthesis inhibitor to suppress HCC both invitro and invivo, highlighting its potential therapeutic applications.

Identification of 8-(2-methyl phenyl)-9H-benzo[f]indeno[2,1-c]quinolin-9-one (C-5635020) as a novel and selective TGFβ RII kinase inhibitor for breast cancer therapy.

Transforming growth factor-beta (TGF-β) plays a pivotal role in breast development by modulating tissue composition during the developmental phase. The TGFβ type II receptor (TGFβ RII) is implicated in breast cancer and represents a valuable therapeutic target. Due to the off-target side effects of many existing TGFβI/TGFβ RII inhibitors, a more targeted approach to drug discovery is necessary. This study used computational modeling and molecular dynamics simulations to screen the ChemBridge small molecule library against TGFβ RII. This study employed high-throughput virtual screening, molecular dynamics simulations, and binding free energy calculations to identify potential inhibitors targeting TGF-β RII. MDA-MB 231 and MCF-7 breast cancer cells were used in anti-proliferative, tans-endothelial migration, and flow cytometric assays for in vitro validations. We identified 8-(2-methylphenyl)-9H-benzo[f]indeno[2,1-c]quinolin-9-one (C-5635020) as a potent and selective inhibitor. Protein-ligand modeling analysis revealed that C-5635020 targets the kinase domain of TGFβ RII with superior binding affinities compared to the standard drug, staurosporine. Computational results suggest that C-5635020 selectively binds and inhibits TGFβ RII activity, thereby controlling cell proliferation in breast cancer. In vitro, experiments corroborated these predictions, where C-5635020 inhibited TGFβ RII and p-Smad 2/3 positive population in MDAMB-231 and MCF-7cells. The compound dose-dependently inhibited cell proliferation, trans-endothelial migration, and increased apoptosis in both breast cancer cell lines. The strong binding affinity, stability, and favorable thermodynamics of C-5635020 with established in vitro efficacy highlight its potential as a lead compound for further preclinical and clinical developments for breast cancer treatment.