POLE -related gene signature predicts prognosis, immune feature, and drug therapy in human endometrioid carcinoma.

The POLE subtype of Endometrial carcinoma (EC) is linked to a favourable prognosis in the molecular classification. We proposed to ascertain the potential connection between the POLE subtype and improved prognosis. In order to forecast the prognosis, least absolute shrinkage and selection operator (LASSO) Cox regression analysis and weighted gene co-expression network analysis (WGCNA) were employed, and a POLE-related risk signature (PRS) model was developed and validated. Single-sample gene set enrichment analysis (ssGSEA) with the "GSVA" package was employed to analyse immunity characteristics. Drug susceptibility studies were conducted to compare the half-maximal inhibitory concentration (IC50) of medicines between high- and low-risk groups. The PRS model was generated employing the LASSO Cox regression coefficients of the ELF1, MMADHC, andAL021707.6 genes. Our study demonstrated that the risk score was linked to tumour stage, grade, and survival. Furthermore, the low-risk group possessed elevated levels of gene expression connected with immunological checkpoints and HLA. Our outcomes emerged that the PRS model might have value in identifying patients with a good prognosis and in facilitating personalised treatment in the clinic.

Current evidence and therapeutic implication of PANoptosis in cancer.

Regulated cell death (RCD) is considered a critical pathway in cancer therapy, contributing to eliminating cancer cells and influencing treatment outcomes. The application of RCD in cancer treatment is marked by its potential in targeted therapy and immunotherapy. As a type of RCD, PANoptosis has emerged as a unique form of programmed cell death (PCD) characterized by features of pyroptosis, apoptosis, and necroptosis but cannot be fully explained by any of these pathways alone. It is regulated by a multi-protein complex called the PANoptosome. As a relatively new concept first described in 2019, PANoptosis has been shown to play a role in many diseases, including cancer, infection, and inflammation. This study reviews the application of PCD in cancer, particularly the emergence and implication of PANoptosis in developing therapeutic strategies for cancer. Studies have shown that the characterization of PANoptosis patterns in cancer can predict survival and response to immunotherapy and chemotherapy, highlighting the potential for PANoptosis to be used as a therapeutic target in cancer treatment. It also plays a role in limiting the spread of cancer cells. PANoptosis allows for the elimination of cancer cells by multiple cell death pathways and has the potential to address various challenges in cancer treatment, including drug resistance and immune evasion. Moreover, active investigation of the mechanisms and potential therapeutic agents that can induce PANoptosis in cancer cells is likely to yield effective cancer treatments and improve patient outcomes. Research on PANoptosis is still ongoing, but it is a rapidly evolving field with the potential to lead to new treatments for various diseases, including cancer.

Insulin-induced gene 2 expression is associated with cervical adenocarcinoma malignant behavior.

BACKGROUND: The incidence of cervical adenocarcinoma (CA) as a malignant tumor has increased over the past few decades due to its low detection rate and malignant biological behaviors. Insulin-induced gene 2 (INSIG2), a membrane protein of the endoplasmic reticulum (ER), plays a crucial role in cancer progression. However, there is little known about the connection between INSIG2 and CA. METHODS: The Human Protein Atlas (HPA) and the Cancer Genome Atlas (TCGA) Cervical Cancer (CESC) data were applied to study the alteration in INSIG2 expression. Biological functions were performed to test the change of malignant behavior. Bioinformatics analysis was conducted to explore the potential affection of INSIG2 in CA progression. RESULTS: Our study confirmed that the high INSIG2 expression levels had a poor prognosis. INSIG2-knockdown inhibited the CA cell proliferation, migration, and invasion of CA cells while downregulating the epithelial-mesenchymal transition (EMT)-associated gene expression levels. Moreover, the enrichment analysis of DEGs showed more potential functions of INSIG2 in the CA progression. CONCLUSION: We found that INSIG2 knockdown may play a suppressor role in the CA progression, and may provide the potential functional influence in inhibiting of CA development.

HDAC2- and EZH2-Mediated Histone Modifications Induce PDK1 Expression through miR-148a Downregulation in Breast Cancer Progression and Adriamycin Resistance.

BACKGROUND: Breast cancer has one of highest morbidity and mortality rates for women. Abnormalities regarding epigenetics modification and pyruvate dehydrogenase kinase 1 (PDK1)-induced unusual metabolism contribute to breast cancer progression and chemotherapy resistance. However, the role and mechanism of epigenetic change in regulating PDK1 in breast cancer remains to be elucidated. METHODS: Gene set enrichment analysis (GSEA) and Pearson's correlation analysis were performed to analyze the relationship between histone deacetylase 2 (HDAC2), enhancer of zeste homologue 2 (EZH2), and PDK1 in database and human breast cancer tissues. Dual luciferase reporters were used to test the regulation between PDK1 and miR-148a. HDAC2 and EZH2 were found to regulate miR-148a expression through Western blotting assays, qRT-PCR and co-immunoprecipitation assays. The effects of PDK1 and miR-148a in breast cancer were investigated by immunofluorescence (IF) assay, Transwell assay and flow cytometry assay. The roles of miR-148a/PDK1 in tumor growth were investigated in vivo. RESULTS: We found that PDK1 expression was upregulated by epigenetic alterations mediated by HDAC2 and EZH2. At the post-transcriptional level, PDK1 was a new direct target of miR-148a and was upregulated in breast cancer cells due to miR-148a suppression. PDK1 overexpression partly reversed the biological function of miR-148a-including miR-148a's ability to increase cell sensitivity to Adriamycin (ADR) treatment-inhibiting cell glycolysis, invasion and epithelial-mesenchymal transition (EMT), and inducing apoptosis and repressing tumor growth. Furthermore, we identified a novel mechanism: DNMT1 directly bound to EZH2 and recruited EZH2 and HDAC2 complexes to the promoter region of miR-148a, leading to miR-148a downregulation. In breast cancer tissues, HDAC2 and EZH2 protein expression levels also were inversely correlated with levels of miR-148a expression. CONCLUSION: Our study found a new regulatory mechanism in which EZH2 and HDAC2 mediate PDK1 upregulation by silencing miR-148a expression to regulate cancer development and Adriamycin resistance. These new findings suggest that the HDAC2/EZH2/miR-148a/PDK1 axis is a novel mechanism for regulating cancer development and is a potentially promising target for therapeutic options in the future.

TBX15/miR-152/KIF2C pathway regulates breast cancer doxorubicin resistance via promoting PKM2 ubiquitination.

BACKGROUND: Chemoresistance is a critical risk problem for breast cancer treatment. However, mechanisms by which chemoresistance arises remains to be elucidated. The expression of T-box transcription factor 15 (TBX-15) was found downregulated in some cancer tissues. However, role and mechanism of TBX15 in breast cancer chemoresistance is unknown. Here we aimed to identify the effects and mechanisms of TBX15 in doxorubicin resistance in breast cancer. METHODS: As measures of Drug sensitivity analysis, MTT and IC50 assays were used in DOX-resistant breast cancer cells. ECAR and OCR assays were used to analyze the glycolysis level, while Immunoblotting and Immunofluorescence assays were used to analyze the autophagy levels in vitro. By using online prediction software, luciferase reporter assays, co-Immunoprecipitation, Western blotting analysis and experimental animals models, we further elucidated the mechanisms. RESULTS: We found TBX15 expression levels were decreased in Doxorubicin (DOX)-resistant breast cancer cells. Overexpression of TBX15 reversed the DOX resistance by inducing microRNA-152 (miR-152) expression. We found that KIF2C levels were highly expressed in DOX-resistant breast cancer tissues and cells, and KIF2C was a potential target of miR-152. TBX15 and miR-152 overexpression suppressed autophagy and glycolysis in breast cancer cells, while KIF2C overexpression reversed the process. Overexpression of KIF2C increased DOX resistance in cancer cells. Furthermore, KIF2C directly binds with PKM2 for inducing the DOX resistance. KIF2C can prevent the ubiquitination of PKM2 and increase its protein stability. In addition, we further identified that Domain-2 of KIF2C played a major role in the binding with PKM2 and preventing PKM2 ubiquitination, which enhanced DOX resistance by promoting autophagy and glycolysis. CONCLUSIONS: Our data identify a new mechanism by which TBX15 abolishes DOX chemoresistance in breast cancer, and suggest that TBX15/miR-152/KIF2C axis is a novel signaling pathway for mediating DOX resistance in breast cancer through regulating PKM2 ubiquitination and decreasing PKM2 stability. This finding suggests new therapeutic target and/or novel strategy development for cancer treatment to overcome drug resistance in the future.

HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth.

Arsenic was recently identified as a pollutant that is a major cause of lung cancer. Since heparin-binding EGF-like growth factor (HB-EGF) was reported to be a promising therapeutic target for lung cancer, we investigated the role and mechanism of HB-EGF during arsenic-induced carcinogenesis and development of lung cancer. HB-EGF expression were upregulated in As-T cells, lung cancer cell lines, and in most lung cancer tissue samples; and HB-EGF activated the EGFR/p-ERK/HIF-1α pathway and induced VEGF by regulating HIF-1α transcription. HIF-1α transcriptional stimulation by HB-EGF was facilitated by PKM2 and played an important role in HB-EGF's effect on cells. An HB-EGF inhibitor(CRM197, cross-reacting material 197) slowed cell proliferation and inhibited migration of As-T and A549 cells, and inhibited tumor growth. PKM2 also played an important role in the proliferation and migration in As-T cells. The positive staining ratios of EGFR phosphorylation (Y1068) and PKM2 were significantly higher in most cases of lung cancer than in paired normal tumor-adjacent lung tissues; and HB-EGF expression levels strongly correlated with p-EGFR expression levels. Thus, HB-EGF drives arsenic-induced carcinogenesis, tumor growth, and lung cancer development via the EGFR/PKM2/HIF-1α pathway.

Mkrn2 deficiency induces teratozoospermia and male infertility through p53/PERP-mediated apoptosis in testis.

The apoptosis that occurs in the immature testis under physiological conditions is necessary for male germ cell development, whereas improper activation of apoptosis can impair spermatogenesis and cause defects in reproduction. We previously demonstrated that in mice, the makorin-2 (Mkrn 2) gene is expressed exclusively in the testis and its deletion leads to male infertility. To understand the potential molecular mechanism, in this study, we found that levels of apoptosis in the testis were abnormally high in the absence of Mkrn 2. To identify specific gene(s) involved, we performed digital gene expression profiling (DGE) and pathway analysis via gene set enrichment analysis (GSEA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and we found that MKRN2 inhibits p53 apoptosis effector related to PMP22 (PERP) expression and that levels of the protein in sperm samples have an inverse correlation with infertility levels. GSEA additionally indicated that PERP is a negative regulator of spermatogenesis and that its ectopic expression induces male infertility. Further, Gene Expression Omnibus (GEO) dataset analysis showed that p53, upstream of PERP, was upregulated in oligoasthenoteratozoospermia (OAT). These observations suggest that Mkrn 2 is crucial for protecting germ cells from excessive apoptosis and implicate Mkrn 2-based suppression of the p53/PERP signaling pathway in spermatogenesis and male fertility.

Estrogen-induced miR-196a elevation promotes tumor growth and metastasis via targeting SPRED1 in breast cancer.

BACKGROUND: Estrogen plays a critical role in breast cancer (BC) progression through estrogen receptor (ER)-mediated gene regulation. Emerging studies suggest that the malignant progress of BC cells is influenced by the cross talk between microRNAs (miRNAs) and ER-α signaling. However, the mechanism and functional linkage between estrogen and miRNAs remain unclear. METHODS: The expression levels of miR-196a and SPRED1 in BC were tested by qRT-PCR in 46 paired BC and adjacent tissues and by the GEO datasets. The role of miR-196a in estrogen-induced BC development was examined by CCK-8 assay, wound healing assay, Matrigel invasion assay and tumorigenicity assay in nude mice. The binding site of ER-α in miR-196a promoter region was analyzed by ChIP-seq, ChIP assay and luciferase reporter assay. The potential targets of miR-196a in BC cells were explored using the luciferase reporter assay and western blot analysis, and the correlation between miR-196a and SPRED1 was analyzed by Spearman's correlation analysis in BC specimens and GEO dataset. TCGA BRCA data was used to characterize the ESR1 signatures according to MSigDB gene set. RESULTS: The expression levels of miR-196a were higher in ER-positive (ER+) breast tumors compared to ER-negative (ER-) tumor tissue samples. Besides, miR-196a was involved in estrogen-induced BC cell proliferation, migration and invasion. Notably, the up-regulation of miR-196a was mediated by a direct interaction with estrogen receptor α (ER-α) but not estrogen receptor ß (ER-ß) in its promoter region, and miR-196a expression levels were positively correlated to ER-α signature scores. Furthermore, SPRED1 was a new direct target of miR-196a which participated in miR-196a-promoted BC development and was suppressed by ligand-activated ER-α signal pathway. Finally, forced expression of miR-196a induced tumor growth of MCF7 cells, while inhibition of miR-196a significantly suppressed the tumor progress in vivo. CONCLUSIONS: Overall, the identification of estrogen/miR-196a/SPRED1 cascade will shed light on new molecular mechanism of estrogen signaling in BC development and therapy.

KLF15 Inhibits Cell Proliferation in Gastric Cancer Cells via Up-Regulating CDKN1A/p21 and CDKN1C/p57 Expression.

BACKGROUND: Krüppel-like factors (KLFs) have been identified in multi-cancers and act as oncogenes or tumor suppressors. The function of KLF15, one member of KLFs, has not been well elucidated, especially in gastric cancer (GC). AIMS: This study was designed to investigate the prognostic value and biological functions of KLF15 in GC. METHODS: KLF15 protein expression in GC patients was evaluated by immunohistochemistry assays in 50 paired GC tissues and adjacent normal tissues, and correlations between KLF15 expression and clinicopathological characteristics and prognosis were analyzed. Then, we investigated the over-expression of KLF15 on cell proliferation and its mechanism in GC cells. RESULTS: KLF15 expression levels were significantly down-regulated in GC tissues compared to adjacent normal tissues. And KLF15 expression was negatively correlated with clinical stage, lymphatic metastasis, and distant metastasis. Furthermore, KLF15 expression could predict prognosis in patients with GC. Moreover, over-expression of KLF15 could inhibit cell proliferation partly via regulating CDKN1A/p21 and CDKN1C/p57. CONCLUSION: These findings demonstrate that KLF15 plays a significant role in GC progression and could be a therapeutic target for GC.

Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis.

It is currently known that estrogen plays an important role in breast cancer (BC) development, but the underlying molecular mechanism remains to be elucidated. Accumulating evidence has revealed important roles of microRNAs in various kinds of human cancers, including BC. In this study, we found that among the microRNAs regulated by estrogen, miR-124 was the most prominent downregulated miRNA. miR-124 was downregulated by estradiol (E2) treatment in estrogen receptor (ER) positive BC cells, miR-124 overexpression suppressed cell proliferation, migration and invasion in BC cells; while the suppression of miR-124 using Anti-miR-124 inhibitor had opposite cellular functions. Under the E2 treatment, miR-124 had stronger effect to inhibit cellular functions in MCF7 cells than that in MDA-MB-231 cells. In addition, we identified that ERα, but not ERß, was required for E2-induced miR-124 downregulation. Furthermore, AKT2, a known oncogene, was a novel direct target of miR-124. AKT2 expression levels were inversely correlated with miR-124 expression levels in human breast cancer specimens. AKT2 was overexpressed in BC specimens, and its expression levels were much higher in ERα positive cancer tissues than those ERα negative cancer tissues. Consistent with miR-124 suppression, E2 treatment increased AKT2 expression levels in MCF7 cells via ERα. Finally, overexpression of miR-124 in MCF7 cells significantly suppressed tumor growth and angiogenesis by targeting AKT2. Our results provide a mechanistic insight into a functional role of new ERα/miR-124/AKT2 signaling pathway in BC development. miR-124 and AKT2 may be used as biomarkers for ERα positive BC and therapeutic effect in the future.