Tumor Suppressor Role Research Articles

Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration

Irregularities in insulin signaling have significantly increased the risk of various cancers, yet the precise underlying mechanisms remain unclear. Within our study, we observed that inhibiting neddylation enhances cancer cell migration across different cancer types by activating both insulin receptor substrates 1 and 2 (IRS1 and IRS2), along with the PI3K/AKT signaling pathway. Notably, in the context of high-grade serous carcinoma (HGSC) patients, whether they had type 2 diabetes mellitus or not, IRS1 and IRS2 displayed a parallel relationship with each other while exhibiting an inverse relationship with NEDD8. We also identified C-CBL as an E3 ligase responsible for neddylating IRS1 and IRS2, with clinical evidence further confirming a reciprocal relationship between C-CBL and pAKT, thereby reinforcing the tumor suppressive role of C-CBL. Altogether, these findings suggest that neddylation genuinely participates in IRS1 and IRS2-dependent insulin signaling, effectively suppressing cancer cell migration. Thus, caution is advised when considering neddylation inhibitors as a treatment option for cancer patients, particularly those presenting with insulin signaling dysregulations linked to conditions like obesity-related type 2 diabetes or hyperinsulinemia.

Ferroptosis heterogeneity within the tumor microenvironment revealed a genetic blueprint of breast cancer.

The tumor microenvironment (TME) significantly influences disease progression through immune infiltration, while ferroptosis, a recently discovered cell death mechanism, plays a crucial role in tumor suppression. However, its role in breast cancer is not clear. In this study, we analyzed bulk RNA and single-cell RNA sequencing data from 1217 samples, including 1104 breast cancer patients and 113 controls, to identify ferroptosis-related genes (FRGs) and construct a prognostic model. Using univariate cox regression, LASSO regression, and multivariate cox regression analysis, we discovered 21 FRGs and 3 TME-related immune cell types with prognostic value. Dimensionality reduction clustering and visualization were performed using the UMAP method, while the immune infiltration process was calculated with the TIP online tool. We employed GSEA enrichment analysis, WGCNA clustering analysis, and correlation analysis to examine functional differences, and the mutation analysis of the best and worst prognosis groups was conducted using the maftools package. Our findings revealed that knocking down the expression of the hub gene SLC39A7 significantly impacted cancer cell apoptosis and combining ferroptosis and TME scores yielded high prognostic power. Epithelial cells and B cells exhibited higher ferroptosis scores, which were independently associated with immune checkpoint blockade (ICB) response and ICB gene expression. This study provides a foundation for further exploration of the relationship between ferroptosis and ICB response in breast cancer. In conclusion, we developed a prognostic model based on ferroptosis and infiltrated immune cells that effectively stratified breast cancer patients and demonstrated the role of SLC39A7 in breast cancer pathogenesis through the regulation of apoptosis.

Regulation of lipid metabolism by APOE4 in intrahepatic cholangiocarcinoma via the enhancement of ABCA1 membrane expression.

Intrahepatic cholangiocarcinoma (ICC) is a malignancy with a dismal prognosis, thus the discovery of promising diagnostic markers and treatment targets is still required. In this study, 1,852 differentially expressed genes (DEGs) were identified in the GSE45001 dataset for weighted gene co-expression network analysis (WGCNA), and the turquoise module was confirmed as the key module. Next, the subnetworks of the 1,009 genes in the turquoise module analyzed by MCODE, MCC, and BottleNeck algorithms identified nine overlapping genes (CAT, APOA1, APOC2, HSD17B4, EHHADH, APOA2, APOE4, ACOX1, AGXT), significantly associated with lipid metabolism pathways, such as peroxisome and cholesterol metabolism. Among them, APOE4 exhibited a potential tumor-suppressive role in ICC and high diagnostic value for ICC in both GSE45001 and GSE32879 datasets. In vitro experiments demonstrated Apolipoprotein E4 (APOE4) overexpression suppressed ICC cell proliferation, migration, and invasion, knockdown was the opposite trend. And in ICC modulated lipid metabolism, notably decreasing levels of TG, LDL-C, and HDL-C, while concurrently increasing the expressions of TC. Further, APOE4 also downregulated lipid metabolism-related genes, suggesting a key regulatory role in maintaining cellular homeostasis, and regulating the expression of the membrane protein ATP-binding cassette transporter A1 (ABCA1). These findings highlighted the coordinated regulation of lipid metabolism by APOE4 and ABCA1 in ICC progression, providing new insights into ICC mechanisms and potential therapeutic strategies.

Abstract B069: Double-stranded RNA derived from tandem repeat sequences induces mesenchymal transition in pancreatic cancer cells by regulating alternative splicing

Abstract Human satellite II (HSATII) composed of tandem repeats in pericentromeric regions in the human genome is aberrantly transcribed in epithelial cancers, particularly pancreatic cancer. Dysregulation of the repetitive elements in cancer tissues can facilitate incidental double-stranded RNA formation. However, it remains controversial whether double-stranded RNAs play tumor-promoting or tumor-suppressing roles during cancer progression. Therefore, we focused on the formation of double-stranded HSATII (dsHSATII) RNA and explored its molecular functions. The overexpression of dsHSATII RNA promoted mesenchymal-like morphological changes and enhanced the invasiveness of pancreatic cancer cells. We identified an RNA-binding protein, STRBP, which preferentially binds to dsHSATII RNA rather than single-stranded HSATII RNA. Depletion of STRBP induced the mesenchymal transition and enhanced the invasiveness. Conversely, the epithelial–mesenchymal transition (EMT) of dsHSATII-expressing cells was rescued by STRBP overexpression. Mechanistically, STRBP is involved in the alternative splicing of genes associated with the EMT events, which was interfered by the overexpression of dsHSATII RNA. Finally, we confirmed that isoform switching of CLSTN1, one of the target genes of STRBP-associated alternative splicing, induced EMT-like morphological changes. These findings reveal a novel cell-autonomous function of dsHSATII RNA in enhancing malignant potential, providing a better understanding of the biological significance of aberrant expression of satellite arrays in malignant tumors. Citation Format: Takahiro Kishikawa, Takuma Iwata, Motoyuki Otsuka, Mitsuhiro Fujishiro. Double-stranded RNA derived from tandem repeat sequences induces mesenchymal transition in pancreatic cancer cells by regulating alternative splicing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B069.

Identification and validation of SLCO4C1 as a biological marker in hepatocellular carcinoma based on anoikis classification features.

Hepatocellular carcinoma (HCC) exhibits a high degree of invasiveness and is closely associated with rapid disease progression. Multiple lines of evidence indicate a strong correlation between anoikis resistance and tumor progression, invasion, and metastasis. Nevertheless, the classification of anoikis in HCC and the investigation of novel biological target mechanisms in this context continue to pose challenges, requiring further exploration. Combined with HCC samples from TCGA, GEO and ICGC databases, cluster analysis was conducted on anoikis genes, revealing novel patterns among different subtypes. Significant gene analysis of different gene subtypes was performed using WCGNA. The anoikis prognostic risk model was established by Lasso-Cox. Go, KEGG, and GSEA were applied to investigate pathway enrichment primarily observed in risk groups. We compared the disparities in immune infiltration, TMB, tumor microenvironment (TME), and drug sensitivity between the two risk groups. RT-qPCR and Western blotting were performed to validate the expression levels of SLCO4C1 in HCC. The biological functions of SLCO4C1 in HCC cells were assessed through various experiments, including CCK8 assay, colony formation assay, invasion migration assay, wound healing assay, and flow cytometry analysis. HCC was divided into 2 anoikis subtypes, and the subtypeB had a better prognosis. An anoikis prognostic model based on 12 (COPZ2, ACTG2, IFI27, SPP1, EPO, SLCO4C1, RAB26, STC2, RAC3, NQO1, MYCN, HSPA1B) risk genes is important for survival and prognosis. Significant differences were observed in immune cell infiltration, TME, and drug sensitivity analysis between the risk groups. SLCO4C1 was downregulated in HCC. SLCO4C1 downregulation promoted the proliferation, invasion, migration, and apoptosis of HCC cells. The tumor-suppressive role of SLCO4C1 in HCC has been confirmed. Our study presents a novel anoikis classification method for HCC that reveals the association between anoikis features and HCC. The anoikis feature is a critical biomarker bridging tumor cell death and tumor immunity. In this study, we provided the first evidence of SLCO4C1 functioning as a tumor suppressor in HCC.

FKBP38 suppresses endometrial cancer cell proliferation and metastasis by inhibiting the mTOR pathway

Endometrial cancer (EC) is a common gynecological malignancy, and advanced-stage or recurrent EC is associated with a high mortality rate owing to the ineffectiveness of currently available treatments. FK506-binding protein 38 (FKBP38) is a member of the immunophilin family and inhibits melanoma and breast cancer cell metastasis. However, the functions of FKBP38 and its potential mechanism in EC remain unclear. Herein, we analyzed the expression levels of FKBP38 in EC cells and found that the FKBP38 expression was high in Ishikawa cells, and low in AN3CA cells, traditionally considered a low grade and a high grade cell line, respectively, in pathology classification. Moreover, FKBP38 inhibited cell proliferation, migration and invasion in EC cells, FKBP38 knockdown significantly promoted tumor growth of Ishikawa cells in a subcutaneous xenograft model and increased the number of lung metastases of Hec-1-A cells in a metastatic mouse model. Furthermore, FKBP38 suppressed several target proteins of epithelial-to-mesenchymal transition (EMT) and reduced the phosphorylation of ribosomal S6 protein (S6), eukaryotic initiation factor 4E-binding protein 1 (4EBP-1), indicating the potent inhibition of the mammalian target of rapamycin (mTOR) pathway. Meanwhile, the inhibition of mTOR neutralized the elevation of EC cell proliferation, migration and invasion after FKBP38 knockdown. In summary, FKBP38 would exert a tumor-suppressing role by modulating the mTOR pathway. Our results indicate that FKBP38 may be considered as a factor of EC metastasis and a new target for EC therapeutic intervention.

ALKBH5 regulates paclitaxel resistance in NSCLC via inhibiting CEMIP-mediated EMT

N6-methyladenosine (m6A) is the most prevalent mRNA modification, and it is verified to be closely correlated with cancer occurrence and progression. The m6A demethylase ALKBH5 (alkB homolog 5) is dysregulated in various cancers. However, the role and underlying mechanism of ALKBH5 in the pathogenesis and especially the chemo-resistance of non-small cell lung cancer (NSCLC) is poorly elucidated. The current study shows that ALKBH5 expression is reduced in paclitaxel (PTX) resistant NSCLC cells and down-regulation of ALKBH5 usually implies poor prognosis of NSCLC patients. Over-expression of ALKBH5 in PTX-resistant cells can suppress cell proliferation and enhance chemo-sensitivity, while knockdown of ALKBH5 exerts the opposite effect, which further supports the tumor suppressive role of ALKBH5. Over-expression of ALKBH5 can also reverse the epithelial-mesenchymal transition (EMT) process in PTX-resistant cancer cells. Mechanistically, data from RNA-seq, real-time PCR and western blotting indicate that CEMIP (cell migration inducing hyaluronidase 1), also known as KIAA1199, may be the downstream target of ALKBH5. Furthermore, ALKBH5 negatively regulates the CEMIP level by reducing the stability of CEMIP mRNA. Collectively, the current data demonstrate that the ALKBH5/CEMIP axis modulates the EMT process in NSCLC, which in turn regulates the chemo-sensitivity of cancer cells to PTX.

Ninjurin 2, a Cell Adhesion Molecule and a Target of p53, Modulates Wild-Type p53 in Growth Suppression and Mutant p53 in Growth Promotion.

The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. However, the biology of NINJ2 has not been well-explored. By using multiple in vitro cell lines and genetically engineered mouse embryo fibroblasts (MEFs), we showed that NINJ2 is induced by DNA damage in a p53-dependent manner. Moreover, we found that the loss of NINJ2 promotes p53 expression via mRNA translation and leads to growth suppression in wild-type p53-expressing MCF7 and Molt4 cells and premature senescence in MEFs in a wild-type p53-dependent manner. Interestingly, NINJ2 also regulates mutant p53 expression, and the loss of NINJ2 promotes cell growth and migration in mutant p53-expressing MIA-PaCa2 cells. Together, these data indicate that the mutual regulation between NINJ2 and p53 represents a negative feedback loop, and the NINJ2-p53 loop has opposing functions in wild-type p53-dependent growth suppression and mutant p53-dependent growth promotion.

Regulation of p53 by the mitotic surveillance/stopwatch pathway: implications in neurodevelopment and cancer.

The transcription factor p53 (encoded by TP53) plays diverse roles in human development and disease. While best known for its role in tumor suppression, p53 signaling also influences mammalian development by triggering cell fate decisions in response to a wide variety of stresses. After over 4 decades of study, a new pathway that triggers p53 activation in response to mitotic delays was recently identified. Termed the mitotic surveillance or mitotic stopwatch pathway, the USP28 and 53BP1 proteins activate p53 in response to delayed mitotic progression to control cell fate and promote genomic stability. In this Minireview, I discuss its identification, potential roles in neurodevelopmental disorders and cancer, as well as explore outstanding questions about its function, regulation and potential use as a biomarker for anti-mitotic therapies.

Protocol for Analyzing Epigenetic Regulation Mechanisms in Breast Cancer.

DNA methylation and gene expression are two critical aspects of the epigenetic landscape that contribute significantly to cancer pathogenesis. Analysis of aberrant genome-wide methylation patterns can provide insights into how these affect the cancer transcriptome and possible clinical implications for cancer diagnosis and treatment. The role of tumor suppressors and oncogenes is well known in tumorigenesis. Epigenetic alterations can significantly impact the expression and function of these critical genes, contributing to the initiation and progression of cancer. This protocol chapter presents a unified workflow to explore the role of DNA methylation in gene expression regulation in breast cancer by identifying differentially expressed genes whose promoter or gene body regions are differentially methylated using various Bioconductor packages in R environment. Functional enrichment analysis of these genes can help in understanding the mechanisms leading to tumorigenesis due to epigenetic alterations.

Evaluacija ekspresije, dijagnostičkog i prognostičkog značaja hsa-miR-675-5p kod oralnog karcinoma

Introduction: Oral cancer is the most common subtype of cancer in the head and neck region, with an increasing incidence worldwide. Unfortunately, no specific biomarkers are used in everyday clinical practice. Small non-coding RNA molecules, microRNA (miRNA), are considered sensitive biomarkers for early diagnosis as well as prognosis in patients with oral cancer. Especially, microRNA derived from the H19 locus are poorly investigated for their potential role in oral cancer. Aim: The aim of this study was to evaluate expression of hsa-miR675-5p in tumor and non-tumor tissues of oral cancer patients and to associate it with pathohistological features. Material and Methods: The study group consisted of 35 patients with oral cancer. Tumor and surrounding non-tumor tissues were taken from each patient. Relative expression was measured using the quantitative reverse transcription - real time PCR method. Results: The relative expression of hsa-miR-675-5p was lower in oral cancer tumor than in non-tumor tissue suggesting its tumor suppressive role. hsa-miR-675-5p has diagnostic potential for sensitive distinction of tumor and non-tumor tissues in oral cancer patients. There was no difference in overall survival rates between patients with low and high hsa-miR-675-5pexpression, confirming that hsa-miR-675-5p cannot be used as a prognostic biomarker in patients with oral cancer. Conclusion: hsa-miR-675-5p can be considered as a potential diagnostic but not a prognostic molecular biomarker in oral cancer.

METTL3 regulates thyroid cancer differentiation and chemosensitivity by modulating PAX8.

Background: Thyroid cancer (TC) is a common endocrine cancer with a favourable prognosis. However, poor patient prognosis due to TC dedifferentiation is becoming an urgent challenge. Recently, methyltransferase-like 3 (METTL3)-mediated N6 -methyladenosine (m6A) modification has been demonstrated to play an important role in the occurrence and progression of various cancers and a tumour suppressor role in TC. However, the mechanism of METTL3 in TC remains unclear. Methods: The correlation between METTL3 and prognosis in TC patients was evaluated by immunohistochemistry. Mettl3fl/flBrafV600ETPO-cre TC mouse models and RNA-seq were used to investigate the underlying molecular mechanism, which was further validated by in vitro experiments. The target gene of METTL3 was identified, and the complete m6A modification process was described. The phenomenon of low expression of METTL3 in TC was explained by identifying miRNAs that regulate METTL3. Results: We observed that METTL3 expression was negatively associated with tumour progression and poor prognosis in TC. Mechanistically, silencing METTL3 promoted the progression and dedifferentiation of papillary thyroid carcinoma (PTC) both in vivo and in vitro. Moreover, overexpressing METTL3 promoted the sensitivity of PTC and anaplastic thyroid cancer (ATC) cells to chemotherapeutic drugs and iodine-131 (131I) administration. Overall, the METTL3/PAX8/YTHDC1 axis has been revealed to play a pivotal role in repressing tumour occurrence, and is antagonized by miR-493-5p.

ETS1 Function in Leukemia and Lymphoma.

ETS proto-oncogene 1 (ETS1) is a transcription factor (TF) critically involved in lymphoid cell development and function. ETS1 expression is tightly regulated throughout differentiation and activation in T-cells, natural killer (NK) cells, and B-cells. It has also been described as an oncogene in a range of solid and hematologic cancer types. Among hematologic malignancies, its role has been best studied in T-cell acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia/lymphoma (ATLL), and diffuse large B-cell lymphoma (DLBCL). Aberrant expression of ETS1 in these malignancies is driven primarily by chromosomal amplification and enhancer-driven transcriptional regulation, promoting the ETS1 transcriptional program. ETS1 also facilitates aberrantly expressed or activated transcriptional complexes to drive oncogenic pathways. Collectively, ETS1 functions to regulate cell growth, differentiation, signaling, response to stimuli, and viral interactions in these malignancies. A tumor suppressor role has also been indicated for ETS1 in select lymphoma types, emphasizing the importance of cellular context in ETS1 function. Research is ongoing to further characterize the clinical implications of ETS1 dysregulation in hematologic malignancies, to further resolve binding complexes and transcriptional targets, and to identify effective therapeutic targeting approaches.

The Diverse Roles of ETV6 Alterations in B-Lymphoblastic Leukemia and Other Hematopoietic Cancers.

Genetic alterations of the repressive ETS family transcription factor gene ETV6 are recurrent in several categories of hematopoietic malignancy, including subsets of B-cell and T-cell acute lymphoblastic leukemias (B-ALL and T-ALL), myeloid neoplasms, and mature B-cell lymphomas. ETV6 is essential for adult hematopoietic stem cells (HSCs), contributes to specific functions of some mature immune cells, and plays a key role in thrombopoiesis as demonstrated by familial ETV6 mutations associated with thrombocytopenia and predisposition to hematopoietic cancers, particularly B-ALL. ETV6 appears to have a tumor suppressor role in several hematopoietic lineages, as demonstrated by recurrent somatic loss-of-function (LoF) and putative dominant-negative alterations in leukemias and lymphomas. ETV6 rearrangements contribute to recurrent fusion oncogenes such as the B-ALL-associated transcription factor (TF) fusions ETV6::RUNX1 and PAX5::ETV6, rare drivers such as ETV6::NCOA6, and a spectrum of tyrosine kinase gene fusions encoding hyperactive signaling proteins that self-associate via the ETV6 N-terminal pointed domain. Another subset of recurrent rearrangements involving the ETV6 gene locus appear to function primarily to drive overexpression of the partner gene. This review surveys what is known about the biochemical and genome regulatory properties of ETV6 as well as our current understanding of how alterations in these functions contribute to hematopoietic and nonhematopoietic cancers.

Transcription factor STAT4 counteracts radiotherapy resistance in breast carcinoma cells by activating the MALAT1/miR-21-5p/THRB regulatory network.

Considering the limited research and the prevailing evidence of STAT4's tumor-suppressing role in breast carcinoma (BC) or in breast radiotherapy (RT) sensitivity requires more in-depth exploration. Our study delves into how STAT4, a transcription factor, affects BC cell resistance to radiotherapy by regulating the MALAT1/miR-21-5p/THRB axis. Bioinformatics analysis was performed to predict the regulatory mechanisms associated with STAT4 in BC. Subsequently, we identified the expression profiles of STAT4, MALAT1, miR-21-5p, and THRB in various tissues and cell lines, exploring their interactions and impact on RT resistance in BC cells. Moreover, animal models were established with X-ray irradiation for further validation. We discovered that STAT4, which is found to be minimally expressed in breast carcinoma (BC) tissues and cell lines, has been associated with a poorer prognosis. In vitro cellular assays indicated that STAT4 could mitigate radiotherapy resistance in BC cells by transcriptional activation of MALAT1. Additionally, MALAT1 up-regulated THRB expression by adsorbing miR-21-5p. As demonstrated in vitro and in vivo, overexpressing STAT4 inhibited miR-21-5p and enhanced THRB levels through transcriptional activation of MALAT1, which ultimately contributes to the reversal of radiotherapy resistance in BC cells and the suppression of tumor formation in nude mice. Collectively, STAT4 could inhibit miR-21-5p and up-regulate THRB expression through transcriptional activation of MALAT1, thereby mitigating BC cell resistance to radiotherapy and ultimately preventing BC development and progression.

Dysregulation of miR-122, miR-574 and miR-375 in Egyptian patients with breast cancer.

The early detection of breast cancer (BC) is receiving global attention, creating an urgent need for more sensitive and comprehensive strategies for preventive intervention, therapy assessment, and prognosis prediction. Aberrant expression of miRNAs has been observed in various malignancies and may be potential targets for therapy. Our study aims to examine the expression profiles of miR-375, miR-574-3p, and miR-122 in the sera of Egyptian women with BC, benign breast lesions, and a control group. We hope to determine if these miRNAs can serve as minimally invasive biomarkers for BC. This is a case-control study in which 77 patients with newly diagnosed BC, 20 patients with benign breast tumors, and 30 normal healthy subjects as controls were recruited from the outpatient clinic of the National Cancer Institute. The assessment of miRNAs was conducted using RT-PCR (Applied Biosystems). The expression level of miRNA-122 was significantly upregulated in the BC group, while the expression levels of miRNA-574 and miRNA-375 showed significant downregulation in BC patients. Serum miR-122 and miRNA-375 were able to distinguish breast cancer from the benign and control groups in ROC curve analysis, with AUCs of 0.786 and 0.796, respectively. Our results also showed that serum miR-122 and miR-574 are significant predictor variables in the multivariate analysis, after adjusting for age. Our findings suggest that miR-122 may act as an onco-microRNA, while miR-574 and miR-375 may have a main tumour suppressor role. The studied miRNAs may serve as minimally invasive biomarkers for cases of breast cancer and as promising potential therapeutic targets for breast cancer.

P53 exerts anticancer effects by regulating enhancer formation and activity.

The abnormality of the p53 tumor suppressor is crucial in lung cancer development, because p53 regulates target gene promoters to combat cancer. Recent studies have shown extensive p53 binding to enhancer elements. However, whether p53 exerts a tumor suppressor role by shaping the enhancer landscape remains poorly understood. In the current study, we employed several functional genomics approaches to assess the enhancer activity at p53 binding sites throughout the genome based on our established TP53 knockout (KO) human bronchial epithelial cells (BEAS-2B). A total of 943 active regular enhancers and 370 super-enhancers (SEs) disappeared upon the deletion of p53, indicating that p53 modulates the activity of hundreds of enhancer elements. We found that one p53-dependent SE, located on chromosome 9 and designated as KLF4-SE, regulated the expression of the Krüppel-like factor 4 ( KLF4) gene. Furthermore, the deletion of p53 significantly decreased the KLF4-SE enhancer activity and the KLF4 expression, but increased colony formation ability in the nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced cell transformation model. Subsequently, in TP53 KO cells, the overexpression of KLF4 partially reversed the increased clonogenic capacity caused by p53 deficiency. Consistently, KLF4 expression also decreased in lung cancer tissues and cell lines. It appeared that overexpression of KLF4 significantly suppressed the proliferation and migration of lung cancer cells. Collectively, our results suggest that the regulation of enhancer formation and activity by p53 is an integral component of the p53 tumor suppressor function. Therefore, our findings offer some novel insights into the regulation mechanism of p53 in lung oncogenesis and introduce a new strategy for screening therapeutic targets.

Expression of RSK4 protein in non-small cell lung cancer tissues, adjacent tissues and its correlation with clinicopathological features.

To evaluate the expression of Ribosomal S6 kinase 4 (RSK4) protein in non-small cell lung cancer (NSCLC) tissues and adjacent non-tumor tissues, and to elucidate its correlation with clinicopathological features of NSCLC. We analyzed 100 NSCLC patients treated at the Second Affiliated Hospital of Zhejiang University School of Medicine from June 2020 to June 2022. Patient demographics and clinical data, including gender, age, history of diabetes, tumor location, degree of tumor differentiation, lymph node metastasis, and clinical stage, were collected. RSK4 protein expression was assessed in tissue samples via immunohistochemical staining. RSK4 protein was positively expressed in 35.00% of cancerous tissues, significantly lower than the 69.00% observed in adjacent non-tumor tissues (P < 0.05). Patients with lower tumor differentiation, advanced Tumor Node Metastasis (TNM) stages, and lymph node metastases showed significantly reduced RSK4 expression compared to those with higher differentiation, earlier TNM stages, and no lymph node metastases (all P < 0.05). Cox regression analysis indicated that TNM stage, low differentiation, and lymph node metastases significantly influenced RSK4 expression (all P < 0.05). Survival analysis revealed a higher positive prognosis survival rate of 74.29% (26/35) among patients with positive RSK4 expression, versus 53.85% (35/65) in those with negative expression (P < 0.05). Spearman correlation analysis demonstrated a significant positive correlation of RSK4 expression with TNM stage, lymph node metastasis, and patient prognosis (all P < 0.05). Positive RSK4 expression in NSCLC tissues is significantly correlated with advanced cancer stage, poor differentiation, and presence of lymph node metastasis, suggesting a potential tumor suppressor role for RSK4 in NSCLC. This association underscores its prognostic relevance in NSCLC patients.

The homeoprotein HOXB2 limits triple-negative breast carcinogenesis via extracellular matrix remodeling.

Homeobox genes and their encoded DNA-binding homeoproteins are master regulators of development. Consequently, these homeotic elements may regulate key steps in cancer pathogenesis. Here, using a combination of in silico analyses of large-scale patient datasets, in vitro RNAi phenotyping, and in vivo validation studies, we investigated the role of HOXB2 in different molecular subtypes of human breast cancer (BC). The gene expression signatures of HOXB2 are different across distinct BC subtypes due to various genetic alterations, but HOXB2 was specifically downregulated in the aggressive triple-negative subtype (TNBC). We found that the reduced expression of HOXB2 was correlated with the metastatic abilities (epithelial-to-mesenchymal transition) of TNBC cells. Further, we revealed that HOXB2 restrained TNBC aggressiveness by ECM organization. HOXB2 bound to the promoter regions of MATN3 and ECM2 and regulated their transcription levels. Forced expression of HOXB2 effectively prevented TNBC progression and metastasis in a mouse xenograft model. Reduction of HOXB2 and the HOXB2/MATN3/ECM2 transcriptional axis correlated with poor survival in patients with various cancers. Further, we found the long non-coding RNA HOXB-AS1 in complex with SMYD3, a lysine methyltransferase, as an epigenetic switch controlling HOXB2 expression. Overall, our results indicate a tumor-suppressive role of HOXB2 by maintaining ECM organization and delineate potential clinical utility of HOXB2 as a marker for TNBC patients.

A novel nanoprobe for visually investigating the controversial role of miRNA-34a as an oncogene or tumor suppressor in cancer cells.

MiRNA-targeted therapy has become a hot topic in current cancer research. The key to this treatment strategy is to clarify the specific role of miRNA in cancer. However, the roles of some miRNAs acting as oncogenic or tumor suppressors are still controversial, which are influenced by different tumor types, even in the same cancer type. Hence, we designed a novel fluorescent nanoprobe based on polydopamine nanoparticles (PDA NPs) for simultaneously detecting caspase-3 and miRNA-34a within living cells. The specific role of miRNA-34a in different cancer cells could be further identified by studying the expression alterations of caspase-3 and miRNA-34a. Confocal imaging indicated that miRNA-34a indeed acted as a tumor suppressor in anticancer drug-treated MCF-7 and HeLa cells, where the effect of miRNA-34a remains controversial. The designed nanoprobe can offer a promising approach to ascertain the oncogenic or tumor-suppressing role of miRNA in different cancer cells with a simple visualization method, which has valuable implications for exploring the practicability of precision therapy focused on miRNA and evaluating the efficacy of new miRNA-targeted anticancer medications.