The role of immune cells settled in the bone marrow on adult hematopoietic stem cells.

Certain immune cells, including neutrophils, macrophages, dendritic cells, B cells, Breg cells, CD4+ T cells, CD8+ T cells, and Treg cells, establish enduring residency within the bone marrow. Their distinctive interactions with hematopoiesis and the bone marrow microenvironment are becoming increasingly recognized alongside their multifaceted immune functions. These cells play a dual role in shaping hematopoiesis. They directly influence the quiescence, self-renewal, and multi-lineage differentiation of hematopoietic stem and progenitor cells through either direct cell-to-cell interactions or the secretion of various factors known for their immunological functions. Additionally, they actively engage with the cellular constituents of the bone marrow niche, particularly mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts, to promote their survival and contribute to tissue repair, thereby fostering a supportive environment for hematopoietic stem and progenitor cells. Importantly, these bone marrow immune cells function synergistically, both locally and functionally, rather than in isolation. In summary, immune cells residing in the bone marrow are pivotal components of a sophisticated network of regulating hematopoiesis.

KLF15 suppresses stemness of pancreatic cancer by decreasing USP21-mediated Nanog stability.

The existence of cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) is considered to be the key factor for metastasis and chemoresistance. Thus, novel therapeutic strategies for eradicating CSCs are urgently needed. Here we aimed to explore the role of KLF15 in stemness and the feasibility of using KLF15 to inhibit CSCs and improve chemotherapy sensitivity in PDAC. In this study, we report that KLF15 is negatively associated with poor survival and advanced pathological staging of PDAC. Moreover, tumorous KLF15 suppresses the stemness of PDAC by promoting the degradation of Nanog, and KLF15 directly interacts with Nanog, inhibiting interaction between Nanog with USP21. We also demonstrate that the KLF15/Nanog complex inhibit the stemness in vivo and in PDX cells. Tazemetostat suppresses stemness and sensitizes PDAC cells to gemcitabine by promoting KLF15 expression in PDAC. In summary, the findings of our study confirm the value of KLF15 level in diagnosis and prognosis of PDAC, it is the first time to explore the inhibition role of KLF15 in stemness of PDAC and the regulation mechanism of Nanog, contributing to provide a new therapeutic strategy that using Tazemetostat sensitizes PDAC cells to gemcitabine by promoting KLF15 expression for PDAC.

Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance.

Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial-mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.

The activation of asparagine synthetase by the transcription factor FOXM1 plays a pivotal role in the initiation and progression of ESCC.

This study explores the role of the transcription factor FOXM1 in the initiation and progression of oesophageal squamous cell carcinoma (ESCC). Our findings reveal that FOXM1 is highly expressed in ESCC and correlates with the prognosis of the disease. The relationship between FOXM1 and asparagine synthetase (ASNS) is investigated, and the study demonstrates that FOXM1 activates ASNS, impacting the tumour stemness of ESCC. In this study, we reveal the association between FOXM1 and ESCC development, as well as FOXM1's promotion of migration and proliferation in ESCC cells. The study also highlights FOXM1's regulation of ASNS transcription and the functional role of ASNS in ESCC metastasis and growth. Furthermore, the study explores the impact of FOXM1 and ASNS on ESCC stemness and their potential implications for chemotherapy resistance.

Treatment-induced stemness and lineage plasticity in driving prostate cancer therapy resistance.

Most human cancers are heterogeneous consisting of cancer cells at different epigenetic and transcriptional states and with distinct phenotypes, functions, and drug sensitivities. This inherent cancer cell heterogeneity contributes to tumor resistance to clinical treatment, especially the molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) and androgen receptor signaling inhibitors (ARSIs). Therapeutic interventions, in turn, induce lineage plasticity (also called lineage infidelity) in cancer cells that also drives therapy resistance. In this Perspective, we focus our discussions on cancer cell lineage plasticity manifested as treatment-induced switching of epithelial cancer cells to basal/stem-like, mesenchymal, and neural lineages. We employ prostate cancer (PCa) as the prime example to highlight ARSI-induced lineage plasticity during and towards development of castration-resistant PCa (CRPC). We further discuss how the tumor microenvironment (TME) influences therapy-induced lineage plasticity. Finally, we offer an updated summary on the regulators and mechanisms driving cancer cell lineage infidelity, which should be therapeutically targeted to extend the therapeutic window and improve patients' survival.

53BP1 regulates the self-renewal ability of neural stem/progenitor cells through modulating mitochondrial homeostasis.

The regulation of intracellular reactive oxygen species (ROS) levels is important for maintaining the self-renewal ability of neural stem/progenitor cells (NSCs). In this study, we demonstrate that 53BP1, a DNA damage response factor known to facilitate the repair of DNA double-strand breaks, supports the maintenance of NSC stemness. ReNcell VM human NSCs with depleted 53BP1 exhibited reduced self-renewal ability compared with control NSCs, as revealed by a decrease in neurosphere size and an increase in differentiation into neural or glial cells within an NSC culture. Furthermore, 53BP1 depletion elevated cellular ROS levels, accompanied by mitochondrial abnormalities. The reduced self-renewal ability and elevated ROS levels in 53BP1-deficient NSCs were restored with the treatment of a radical scavenger, N-acetyl-l-cysteine. In addition, we investigated the functional relationship in the NSC self-renewal ability between 53BP1 and ataxia-telangiectasia mutated (ATM) or forkhead box O3a (FOXO3a), factors required for mitochondrial homeostasis, and the maintenance of NSC stemness. We found that ATM inhibition or FOXO3a deficiency, in addition to 53BP1 deficiency, did not induce further NSC stemness impairment. Collectively, our findings show that 53BP1, by cooperatively functioning with ATM and FOXO3a, supports the maintenance of NSC stemness by modulating mitochondrial homeostasis.

Recent update on IGF-1/IGF-1R signaling axis as a promising therapeutic target for triple-negative breast cancer.

Insulin-like growth factor 1/Insulin-like growth factor 1-receptor (IGF-1/IGF-1R) pathway is highly breast cancer subtype context-dependent. Triple-negative breast cancer (TNBC) is an aggressive, highly metastatic cancer showing early recurrence and poor prognosis. High expression of IGF-1 and its receptor IGF-1R, their interaction, autophosphorylation, and activation of intracellular signaling cascades have been significantly associated with TNBC pathophysiology. In the last five to seven years, marvelous work has been done to explore the role of IGF-1/IGF-1R axis in TNBC. In the present review, starting from the general introduction to IGF-1/IGF-1R pathway an up-to-date discussion was focused on its role in TNBC pathophysiology. Further we discussed the up/down stream molecular events of IGF-1/IGF-1R axis, clinical relevance of IGF-1 and IGF-1R levels in TNBC patients, anti-TNBC therapy and possible way-out for IGF-1/IGF-1R axis mediate therapy resistance in TNBC. Combination therapy strategy has been researched to overcome direct IGF-1/IGF-1R pathway inhibition mediated therapy resistance and produced promising results in the management of TNBC. The understanding of up/downstream of the IGF-1/IGF-1R axis provide immense focus on the pathway as a therapeutic target. It is expected within the next decade to determine its potentiality, or lack thereof, for TNBC treatment.

Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFß and Hedgehog signal pathway.

PURPOSE: Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug. METHOD: The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance. RESULTS: ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFß and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC. CONCLUSIONS: These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFß, Hedgehog axis.

Pressure loading regulates the stemness of liver cancer stem cells via YAP/BMF signaling axis.

Cancer stem cells (CSCs) are considered the major cause of the occurrence, progression, chemoresistance/radioresistance, recurrence, and metastasis of cancer. Increased interstitial fluid pressure (IFP) is a key feature of solid tumors. Our previous study showed that the distribution of liver cancer stem cells (LCSCs) correlated with the mechanical heterogeneity within liver cancer tissues. However, the regulation of liver cancer's mechanical microenvironment on the LCSC stemness is not fully understood. Here, we employed a cellular pressure-loading device to investigate the effects of normal IFP (5 mmHg), as well as increased IFP (40 and 200 mmHg) on the stemness of LCSCs. Compared to the control LCSCs (exposure to 5 mmHg pressure loading), the LCSCs exposed to 40 mmHg pressure loading exhibited significantly upregulated expression of CSC markers (CD44, EpCAM, Nanog), enhanced sphere and colony formation capacities, and tumorigenic potential, whereas continuously increased pressure to 200 mmHg suppressed the LCSC characteristics. Mechanistically, pressure loading regulated Yes-associated protein (YAP) activity and Bcl-2 modifying factor (BMF) expression. YAP transcriptionally regulated BMF expression to affect the stemness of LCSCs. Knockdown of YAP and overexpression of BMF attenuated pressure-mediated stemness and tumorgenicity, while YAP-deficient and BMF-deletion recused pressure-dependent stemness on LCSCs, suggesting the involvement of YAP/BMF signaling axis in this process. Together, our findings provide a potential target for overcoming the stemness of CSCs and elucidate the significance of increased IFP in cancer progression.

The SIX2/PFN2 feedback loop promotes the stemness of gastric cancer cells.

BACKGROUND: The roles of the transcriptional factor SIX2 have been identified in several tumors. However, its roles in gastric cancer (GC) progression have not yet been revealed. Our objective is to explore the impact and underlying mechanisms of SIX2 on the stemness of GC cells. METHODS: Lentivirus infection was employed to establish stable expression SIX2 or PFN2 in GC cells. Gain- and loss-of-function experiments were conducted to detect changes of stemness markers, flow cytometry profiles, tumor spheroid formation, and tumor-initiating ability. ChIP, RNA-sequencing, tissue microarray, and bioinformatics analysis were performed to reveal the correlation between SIX2 and PFN2. The mechanisms underlying the SIX2/PFN2 loop-mediated effects were elucidated through tissue microarray analysis, RNA stability assay, IP-MS, Co-Immunoprecipitation, and inhibition of the JNK signaling pathway. RESULTS: The stemness of GC cells was enhanced by SIX2. Mechanistically, SIX2 directly bound to PFN2's promoter and promoted PFN2 activity. PFN2, in turn, promoted the mRNA stability of SIX2 by recruiting RNA binding protein YBX-1, subsequently activating the downstream MAPK/JNK pathway. CONCLUSION: This study unveils the roles of SIX2 in governing GC cell stemness, defining a novel SIX2/PFN2 regulatory loop responsible for this regulation. This suggests the potential of targeting the SIX2/PFN2 loop for GC treatment (Graphical Abstracts).

Promotion of hepatocellular carcinoma stemness and progression by abnormal spindle-like microcephaly-associated protein via the Wnt/ß-catenin pathway.

Background: Cancer stem cells (CSCs) play a crucial role in tumor recurrence and metastasis, which are the primary causes of death in patients with hepatocellular carcinoma (HCC). Currently, no drug effectively blocks the recurrence and metastasis of liver cancer, leading to a poor prognosis for patients. To enhance treatment outcomes, there is an urgent need to investigate the molecular mechanisms behind the recurrence and progression of liver cancer, with the aim of identifying effective therapeutic targets. Targeting HCC stemness can improve the prognosis of patients with HCC. Abnormal spindle-like microcephaly-associated protein (ASPM) plays a pivotal role in regulating neurogenesis and brain size, which is a centrosome protein. ASPM has been implicated in tumorigenesis and tumor progression, but its regulatory role in HCC stemness is not well understood. This study aims to investigate the role of ASPM in liver cancer stemness and elucidate its potential molecular mechanisms. Methods: Bioinformatics analysis was used to study the expression of ASPM and its clinical significance in HCC. In vitro and in vivo assays were conducted to clarify the impact of ASPM knockdown on HCC cell stemness. The correlation between ASPM and the Wnt/ß-catenin pathway was examined through analysis of online databases and in vitro experiments. Results: The bioinformatics analysis revealed significant upregulation of ASPM was significantly upregulated in HCC samples, with expression correlating with poor prognosis. In vitro experimental data confirmed elevated ASPM expression in HCC cells compared to normal hepatocytes. Knockdown of ASPM suppressed HCC cell growth, clone formation, spheroid formation, migration, invasion, and the expression of CSC markers CD133 and CD44. This also inhibited the activation of the Wnt/ß-catenin pathway. Reactivation of this pathway partially reversed the biological changes induced by ASPM knockdown in HCC cells. Additionally, in vivo data demonstrated that ASPM downregulation reduced the size and weight of xenografts in BALB/c mice, along with decreased expression of CSC markers. Conclusions: These findings suggest that ASPM promotes HCC stemness and progression through the Wnt/ß-catenin pathway. Targeting ASPM or the Wnt/ß-catenin pathway may be a promising strategy to prevent HCC chemoresistance and recurrence, ultimately improving patient prognosis.

Casticin suppresses self-renewal related stemness via miR-342-3p-mediated FoxM1 downregulation in cervical cancer cells.

BACKGROUND: Casticin (CAS), a natural flavonoid found in Viticis Fructus, Viticis Cannabifoliae Fructus, and Semen Euphorbiae, shows anti-inflammatory activity and efficacy against various cancers. However, its effect on stemness associated with self-renewal in cervical cancer (CC) cells remains unclear, as well as the underlying mechanism. PURPOSE: The primary objective of this study was to examine the effect of CAS on CC stemness and to explore the underpinning regulatory mechanism. METHODS: HeLa cells underwent treatment with varying concentrations of CAS (0, 10, 30, 100 nM). To evaluate the impacts of CAS on CC stemness and tumorigenicity, sphere- and colony-formation assays and a xenograft model were employed. The study involved screening for changes in miRNAs and their target genes. The miRNA array identified an upregulation in miRNAs, whereas the mRNA array detected a downregulation of specific target genes. The latter genes were found to regulate stem cell-related genes through miR-342-3p in HeLa cells administered CAS. Next, whether miR-342-3p directly targets FOXM1 when upregulated by CAS was assessed by the luciferase reporter assay. qRT-PCR was performed to analyze miR-342-3p expression. Additionally, immunoblotting was conducted to assess the protein amounts of FoxM1 and stemness-related factors (CD133, CD49f, Nanog, and Sox2). Function rescue experiments were conducted to determine the mechanism of CAS in stemness regulation. These experiments involved utilizing a miR-342-3p inhibitor and overexpressing FOXM1 in HeLa cells. RESULTS: CAS decreased in vitro stemness, suppressing sphere- and colony-formation capabilities of CC. It also dose-dependently downregulated the expression of stemness-associated proteins, including CD133, CD49f, Nanog, and Sox2. Moreover, CAS inhibited in vivo carcinogenesis, remarkably reducing tumor growth in mice bearing HeLa cell xenografts. Analysis revealed downregulated FOXM1 expression in HeLa cells treated with CAS. In the luciferase reporter assay, miR-342-3p was found to directly target FOXM1 in CAS-treated HeLa cells. Additionally, miR-342-3p inhibitor transfection successfully rescued CAS' suppressive impact on stemness. Furthermore, overexpression of FOXM1 did not induce changes in miR-342-3p expression. However, it effectively rescued CAS' suppressive effects on stemness. Moreover, CAS also inhibited stemness, upregulated miR-342-3p, and lowered FOXM1 expression in the SiHa cell line. CONCLUSION: CAS suppresses self-renewal-associated stemness by targeting FOXM1 via miR-342-3p upregulation. These findings suggest CAS is promising as a novel therapeutic candidate in CC.

Modulation of osteoblastogenesis by NRF2: NRF2 activation suppresses osteogenic differentiation and enhances mineralization in human bone marrow-derived mesenchymal stromal cells.

Mesenchymal stromal stem cells (MSCs) or skeletal stem cells (SSCs) play a major role in tissue repair due to their robust ability to differentiate into osteoblasts, chondrocytes, and adipocytes. Complex cell signaling cascades tightly regulate this differentiation. In osteogenic differentiation, Runt-related transcription factor 2 (RUNX2) and ALP activity are essential. Furthermore, during the latter stages of osteogenic differentiation, mineral formation mediated by the osteoblast occurs with the secretion of a collagenous extracellular matrix and calcium deposition. Activation of nuclear factor erythroid 2-related factor 2 (NRF2), an important transcription factor against oxidative stress, inhibits osteogenic differentiation and mineralization via modulation of RUNX2 function; however, the exact role of NRF2 in osteoblastogenesis remains unclear. Here, we demonstrate that NRF2 activation in human bone marrow-derived stromal cells (HBMSCs) suppressed osteogenic differentiation. NRF2 activation increased the expression of STRO-1 and KITLG (stem cell markers), indicating NRF2 protects HBMSCs stemness against osteogenic differentiation. In contrast, NRF2 activation enhanced mineralization, which is typically linked to osteogenic differentiation. We determined that these divergent results were due in part to the modulation of cellular calcium flux genes by NRF2 activation. The current findings demonstrate a dual role for NRF2 as a HBMSC maintenance factor as well as a central factor in mineralization, with implications therein for elucidation of bone formation and cellular Ca2+ kinetics, dystrophic calcification and, potentially, application in the modulation of bone formation.

Leucine drives LAT1-related SNAIL upregulation in glucose-starved pancreatic cancer cells.

Pancreatic cancer, a highly fibrotic and hypovascular tumor, is thought to have unique metabolic characteristics in surviving and proliferating in malnutritional microenvironments. In this study, we compared the differences in the ability of pancreatic cancer cells to adapt to glucose-free conditions with liver cancer cells, which are representative of hypervascular tumors. Three pancreatic cancer cells and two liver cancer cells were used to examine the transcriptional expression levels of molecules involved in intracellular amino acid uptake, epithelial-mesenchymal transition (EMT), and cancer stemness under glucose deprivation. The results showed that the proliferative activity of pancreatic cancer cells under glucose deprivation was significantly lower than that of liver cancer cells, but the expression levels of amino acid transporters were significantly higher. Among them, L-type amino acid transporter 1 (LAT1) upregulation was unique in concert with increased expression of the EMT regulator SNAIL and the cancer stemness marker doublecortin-like kinase 1. LAT1 knockdown canceled the upregulation of SNAIL in glucose-starved pancreatic cancer cells, suggesting a mechanistic link between the two molecules. When LAT1 was stimulated by its substrate leucine, the SNAIL expression was upregulated dose-dependently. Collectively, pancreatic cancer cells reprogrammed metabolism to adapt to energy crises involving leucine-induced SNAIL upregulation.

Integrins in cancer stem cells.

Integrins are a class of adhesion receptors on cell membranes, consisting of α and ß subunits. By binding to the extracellular matrix, integrins activate intracellular signaling pathways, participating in every step of cancer initiation and progression. Tumor stem cells possess self-renewal and self-differentiation abilities, along with strong tumorigenic potential. In this review, we discussed the role of integrins in cancer, with a focus on their impact on tumor stem cells and tumor stemness. This will aid in targeting tumor stem cells as a therapeutic approach, leading to the exploration of novel cancer treatment strategies.

TRIM24/ZFX affects the stemness and resistance to 5-FU of colorectal cancer cells.

Colorectal cancer (CRC) is the second leading cause of cancer death, and about 10% of all malignancies are CRC. Cancer stem cells are considered main culprits in CRC treatment resistance and disease recurrence. This study explored the effects of tripartite motif containing 24 (TRIM24) and zinc finger protein, X-linked (ZFX) on CRC cell stemness and 5-FU resistance. A 5-FU-resistant cell line (HT29-5-FU) was constructed for functional analysis of CRC 5-FU-resistant cells. qRT-PCR and western blot (WB) were employed to analyze mRNA and protein levels of ZFX in 5-FU resistant cells and sensitive cells. WB was also utilized to analyze the surface markers of stem cells in each group. CCK-8 assay determined the IC50 values of different cell groups treated with 5-FU. The sphere-forming ability of cells in each group was determined using tumor sphere assay. Dual-luciferase reporter gene assay validated binding of ZFX to TRIM24. ZFX was highly expressed in HT29-5-FU cells. Silencing ZFX significantly reduced the 5-FU resistance and IC50 value of HT29-5-FU cells, and the surface markers and cell sphere-forming ability of stem cells were also significantly reduced. The function of HT29 cells was opposite when ZFX was overexpressed. In CRC cells, TRIM24 was an upstream transcription factor of ZFX, and they interacted with each other. TRIM24 activated the expression of ZFX to influence the stemness and 5-FU resistance of cells. The TRIM24/ZFX regulatory axis affected the stemness of CRC cells and their sensitivity to 5-FU, providing potential drug targets for novel therapeutic avenues for CRC.

PDCD10 Is a Key Player in TMZ-Resistance and Tumor Cell Regrowth: Insights into Its Underlying Mechanism in Glioblastoma Cells.

Overcoming temozolomide (TMZ)-resistance is a major challenge in glioblastoma therapy. Therefore, identifying the key molecular player in chemo-resistance becomes urgent. We previously reported the downregulation of PDCD10 in primary glioblastoma patients and its tumor suppressor-like function in glioblastoma cells. Here, we demonstrate that the loss of PDCD10 causes a significant TMZ-resistance during treatment and promotes a rapid regrowth of tumor cells after treatment. PDCD10 knockdown upregulated MGMT, a key enzyme mediating chemo-resistance in glioblastoma, accompanied by increased expression of DNA mismatch repair genes, and enabled tumor cells to evade TMZ-induced cell-cycle arrest. These findings were confirmed in independent models of PDCD10 overexpressing cells. Furthermore, PDCD10 downregulation led to the dedifferentiation of glioblastoma cells, as evidenced by increased clonogenic growth, the upregulation of glioblastoma stem cell (GSC) markers, and enhanced neurosphere formation capacity. GSCs derived from PDCD10 knockdown cells displayed stronger TMZ-resistance and regrowth potency, compared to their parental counterparts, indicating that PDCD10-induced stemness may independently contribute to tumor malignancy. These data provide evidence for a dual role of PDCD10 in tumor suppression by controlling both chemo-resistance and dedifferentiation, and highlight PDCD10 as a potential prognostic marker and target for combination therapy with TMZ in glioblastoma.

Transcription factor Yin Yang 1 enhances epithelial-mesenchymal transition, migration, and stemness of non-small cell lung cancer cells by targeting sonic hedgehog.

Non-small cell lung cancer (NSCLC) is a frequent type of lung cancer. Transcription factor Yin Yang 1 (YY1), an endogenous transcription factor containing zinc finger structure, can accelerate NSCLC progression. However, the impact of YY1 on the stemness of NSCLC cells and the mechanism of promoting NSCLC cell progression is unclear. YY1 and Sonic hedgehog (Shh) expressions were monitored by RT-qPCR, western blot, and immunohistochemistry. Overall survival was tested through Kaplan-Meier analysis. The interaction between YY1 and Shh was confirmed. Then, cell migration, stemness, and epithelial-mesenchymal transition (EMT) were assessed with functional experiments in vitro and in vivo. YY1 and Shh were highly expressed in NSCLC tissues and positively correlated with the poor OS of NSCLC patients. Functional experiments denoted that YY1 or Shh overexpression could accelerate EMT, migration, and stemness of NSCLC cells, and YY1 or Shh knockdown played the opposite role to its overexpression. Mechanism analysis disclosed that Shh, as a target gene of YY1, was positively related to YY1. The rescued experiment manifested that Shh silencing could reverse the induction effect of YY1 overexpression on EMT, migration, and stemness of NSCLC cells. In vivo experiments also confirmed that YY1 could accelerate tumor growth and EMT and weaken apoptosis. YY1 promotes NSCLC EMT, migration, and stemness by Shh, which might be novel diagnostic markers and therapeutic targets for NSCLC therapy.

E-cigarettes increase the risk of adenoma formation in murine colorectal cancer model.

Background: E-cigarettes (E.cigs) cause inflammation and damage to human organs, including the lungs and heart. In the gut, E.cig vaping promotes inflammation and gut leakiness. Further, E.cig vaping increases tumorigenesis in oral and lung epithelial cells by inducing mutations and suppressing host DNA repair enzymes. It is well known that cigarette (cig) smoking increases the risk of colorectal cancer (CRC). To date, it is unknown whether E.cig vaping impacts CRC development. Methods: A mouse model of human familial adenomatous polyposis (CPC-APC) was utilized wherein a mutation in the adenomatous polyposis coli (APC) gene, CDX2-Cre-APCMin/+, leads to the development of colon adenomas within 16 weeks. Mice were exposed to air (controls), E.cig vaping, cig, or both (dual exposure). After 4 weeks of 2-hour exposures per day (1 hour of each for dual exposures), the colon was collected and assessed for polyp number and pathology scores by microscopy. Expression of inflammatory cytokines and cancer stem cell markers were quantified. DNA damage such as double-strand DNA breaks was evaluated by immunofluorescence, western blot and gene-specific long amplicon qPCR. DNA repair enzyme levels (NEIL-2, NEIL-1, NTH1, and OGG1) were quantified by western blot. Proliferation markers were assessed by RT-qPCR and ELISA. Results: CPC-APC mice exposed to E.cig, cig, and dual exposure developed a higher number of polyps compared to controls. Inflammatory proteins, DNA damage, and cancer stemness markers were higher in E-cig, cig, and dual-exposed mice as well. DNA damage was found to be associated with the suppression of DNA glycosylases, particularly with NEIL-2 and NTH1. E.cig and dual exposure both stimulated cancer cell stem markers (CD44, Lgr-5, DCLK1, and Ki67). The effect of E.cigs on polyp formation and CRC development was less than that of cigs, while dual exposure was more tumorigenic than either of the inhalants alone. Conclusion: E.cig vaping promotes CRC by stimulating inflammatory pathways, mediating DNA damage, and upregulating transcription of cancer stem cell markers. Critically, combining E.cig vaping with cig smoking leads to higher levels of tumorigenesis. Thus, while the chemical composition of these two inhalants, E.cigs and cigs, is highly disparate, they both drive the development of cancer and when combined, a highly common pattern of use, they can have additive or synergistic effects.

Clinical application and immune infiltration landscape of stemness-related genes in heart failure.

BACKGROUND: Heart failure (HF) is the leading cause of morbidity and mortality worldwide. Stemness refers to the self-renewal and differentiation ability of cells. However, little is known about the heart's stemness properties. Thus, the current study aims to identify putative stemness-related biomarkers to construct a viable prediction model of HF and characterize the immune infiltration features of HF. METHODS: HF datasets from the Gene Expression Omnibus (GEO) database were adopted as the training and validation cohorts while stemness-related genes were obtained from GeneCards and previously published papers. Feature selection was performed using two machine learning algorithms. Nomogram models were then constructed to predict HF risk based on the selected key genes. Moreover, the biological functions of the key genes were evaluated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) pathway analyses, and gene set variation analysis (GSVA) and enrichment analysis (GSEA) were performed between the high- and low-risk groups. The immune infiltration landscape in HF was investigated, and the interaction network of key genes was analysed to predict potential targets and molecular mechanisms. RESULTS: Seven key genes, namely SMOC2, LUM, FNDC1, SCUBE2, CD163, BLM and S1PR3, were included in the proposed nomogram. This nomogram showed good predictive performance for HF diagnosis in the training and validation sets. GO and KEGG analyses revealed that the key genes were primarily associated with ageing, inflammatory processes and DNA oxidation. GSEA and GSVA identified various inflammatory and immune signalling pathways that were enriched between the high- and low-risk groups. The infiltration of 15 immune cell subsets suggests that adaptive immunity has an important role in HF. CONCLUSIONS: Our study identified a clinically significant stemness-related signature for predicting HF risk, with the potential to improve early disease diagnosis, optimize risk stratification and provide new strategies for treating patients with HF.