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Ovarian cancer (OC) is one of the most common malignancies that causes death in women and is a heterogeneous disease with complex molecular and genetic changes. Because of the relatively high recurrence rate of OC, it is crucial to understand the associated mechanisms of drug resistance and to discover potential target for rational targeted therapy. Cell death is a genetically determined process. Active and orderly cell death is prevalent during the development of living organisms and plays a critical role in regulating life homeostasis. Ferroptosis, a novel type of cell death discovered in recent years, is distinct from apoptosis and necrosis and is mainly caused by the imbalance between the production and degradation of intracellular lipid reactive oxygen species triggered by increased iron content. Necroptosis is a regulated non-cysteine protease–dependent programmed cell necrosis, morphologically exhibiting the same features as necrosis and occurring via a unique mechanism of programmed cell death different from the apoptotic signaling pathway. Pyroptosis is a form of programmed cell death that is characterized by the formation of membrane pores and subsequent cell lysis as well as release of pro-inflammatory cell contents mediated by the abscisin family. Studies have shown that ferroptosis, necroptosis, and pyroptosis are involved in the development and progression of a variety of diseases, including tumors. In this review, we summarized the recent advances in ferroptosis, necroptosis, and pyroptosis in the occurrence, development, and therapeutic potential of OC.

Purpose: TERT promoter mutation (TERTpMut) has a strong association to recurrence and has been suggested to act as a driver mutation for malignant transformation of WHO grade I and II meningiomas. TERTpMut has been investigated in selected high‐grade meningioma samples. The existence of TERTpMut across recurrent tumors in a population‐based cohort needs to be investigated in order to identify when TERTpMut emerges across recurrent samples and to validate prognostic impact among WHO grade III tumors. Methods: We gathered material from a consecutive single‐center cohort of 40 patients with malignant meningioma (WHO grade III) treated between 2000 and 2018, including specimens from primary and secondary malignant meningiomas with the corresponding earlier benign specimens and later malignant recurrences. In total 107 tumor samples were studied by Sanger sequencing for TERT promoter mutational status. Results: Seven of 40 patients (17.5%) harbored TERTpMut thus validating the incidence of TERTpMut in previous non‐population‐based cohorts. In 6/7 patients, the TERTpMut was present at initial surgery (WHO grade I–III) while in one patient the TERTpMut was found de novo when the meningioma became malignant. The incidences were 2/1.000.000/year for TERTpMut WHO grade III meningioma and 8/1.000.000/year for TERTpwt WHO grade III meningioma in our catchment area. We found a 1.7 times higher recurrence rate (CI 95% 0.65–4.44) and a 2.5 higher mortality rate per 10 person‐years (CI 95% 1.01–6.19) for TERTpMut compared to TERTpwt. Conclusion: TERTpMut can occur independently of malignant progression in meningioma and was most often present from the first tumor sample across recurring tumors. TERTpMut in WHO grade III may represent a marker of an aggressive subset of tumors. We investigated the TERT promoter mutation (TERTpMut) in a population‐based, consecutive cohort of 40 malignant meningioma patients with tumor samples available from the corresponding earlier benign specimens and later malignant recurrences. TERTpMut can occur independently of malignant progression in meningioma and was most often present from the first tumor sample across recurring tumors. TERTpMut in WHO grade III may represent a marker of an aggressive subset of tumors.

miRNAs (microRNAs) have been validated to play fateful roles in the occurrence and development of cancers by post-transcriptionally targeting 3′-untranslated regions of the downstream gene mRNAs to repress mRNA expression. Mounting investigations forcefully document that not only does miR-22 biologically impinge on the processes of senescence, energy supply, angiogenesis, EMT (epithelial-mesenchymal transition), proliferation, migration, invasion, metastasis and apoptosis, but also it genetically or epigenetically exerts dual (inhibitory/promoting cancer) effects in various cancers via CNAs (copy number alterations), SNPs (single nucleotide polymorphisms), methylation, acetylation and even more momentously hydroxymethylation. Additionally, miR-22 expression may fluctuate with cancer progression in the body fluids of cancer patients and miR-22 could amplify its inhibitory or promoting effects through partaking in positive or negative feedback loops and interplaying with many other related miRNAs in the cascade of events, making it possible for miR-22 to be a promising and complementary or even independent cancer biomarker in some cancers and engendering profound influences on the early diagnosis, therapeutics, supervising curative effects and prognosis.

Y‐box binding protein‐1 (YBX1), a multifunctional oncoprotein containing an evolutionarily conserved cold shock domain, dysregulates a wide range of genes involved in cell proliferation and survival, drug resistance, and chromatin destabilization by cancer. Expression of a multidrug resistance‐associated ATP binding cassette transporter gene, ABCB1, as well as growth factor receptor genes, EGFR and HER2/ErbB2, was initially discovered to be transcriptionally activated by YBX1 in cancer cells. Expression of other drug resistance‐related genes, MVP/LRP, TOP2A, CD44, CD49f, BCL2, MYC, and androgen receptor (AR), is also transcriptionally activated by YBX1, consistently indicating that YBX1 is involved in tumor drug resistance. Furthermore, there is strong evidence to support that nuclear localization and/or overexpression of YBX1 can predict poor outcomes in patients with more than 20 different tumor types. YBX1 is phosphorylated by kinases, including AKT, p70S6K, and p90RSK, and translocated into the nucleus to promote the transcription of resistance‐ and malignancy‐related genes. Phosphorylated YBX1, therefore, plays a crucial role as a potent transcription factor in cancer. Herein, a novel anticancer therapeutic strategy is presented by targeting activated YBX1 to overcome drug resistance and malignant progression. The oncogenic Y‐box binding protein‐1, YBX1, is a DNA/RNA binding multifunctional protein and YBX1 has recently been highlighted as a compelling therapeutic target. Enhanced expression of YBX1 in the nucleus and/or cytoplasm of cancer cells can also predict poor outcomes in more than 20 different tumor types including breast, lung, ovarian, prostate, and others. Furthermore, various research groups have recently started to develop novel and potent therapeutic drugs against progressive cancers by targeting YBX1.

Lung cancer remains one of the major causes of cancer-related death globally. Recent studies have shown that aberrant m 6 A levels caused by METTL3 are involved in the malignant progression of various tumors, including lung cancer. The m 6 A modification, the most abundant RNA chemical modification, regulates RNA stabilization, splicing, translation, decay, and nuclear export. The methyltransferase complex plays a key role in the occurrence and development of many tumors by installing m 6 A modification. In this complex, METTL3 is the first identified methyltransferase, which is also the major catalytic enzyme. Recent findings have revealed that METTL3 is remarkably associated with different aspects of lung cancer progression, influencing the prognosis of patients. In this review, we will focus on the underlying mechanism of METT3 in lung cancer and predict the future work and potential clinical application of targeting METTL3 for lung cancer therapy.

Tumor-associated macrophages (TAMs) are pivotal components of the immune cell infiltrate in tumors and cell division cycle-associated protein-3 (CDCA3) is associated with tumor progression. The role of CDCA3 in regulating TAM polarization remains uncharacterized in hepatocellular carcinoma (HCC). CDCA3 expression, its correlation with immune cell infiltration, and prognostic significance in HCC were analyzed using the TCGA and TIMER databases. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), were performed to predict CDCA3-related pathways. The knockdown efficiency of CDCA3 in HCC cell lines was confirmed by RT-qPCR and Western blotting. Functional assays, including CCK-8, wound healing, and flow cytometry, were used to assess the role of CDCA3 in cell proliferation, migration, and apoptosis. Immunohistochemistry (IHC) was applied to evaluate the correlation between CDCA3 expression and M2 macrophage markers in clinical tissue samples. Bioinformatic analysis revealed that CDCA3 was significantly upregulated in HCC tissues, and its high expression was associated with advanced clinical stage, higher tumor grade, and poor prognosis. CDCA3 expression also correlated strongly with the level of immune infiltration. Notably, CDCA3 showed high diagnostic potential for HCC, with an area under the curve (AUC) of 0.869, cut-off value of 189.03 pg/mL, sensitivity of 81.9%, and specificity of 77.8%. Experimentally, CDCA3 knockdown significantly suppressed malignant phenotypes of HCC cells and inhibited M2 macrophage polarization. Our findings suggest that CDCA3 promotes the malignant progression of HCC by driving M2-like TAM polarization, potentially through the upregulation of cytokines such as TGF-β1, VEGFA, CD40, CXCL1, and CXCL5. CDCA3 thus represents a promising diagnostic biomarker and therapeutic target for HCC.

Colorectal cancer (CRC) progression critically depends on the tumor microenvironment. PLOD2, an enzyme involved in collagen biosynthesis, is highly expressed in many cancers. While it promotes CRC growth via the USP15–AKT/mTOR pathway, its role in enhancing tumor cell migration and invasion remains unclear. Our study identified a significant upregulation of PLOD2 in colorectal cancer. This upregulation was closely associated with clinical stage, lymph node metastasis, and nerve invasion in CRC. Functional assays, including CCK-8, colony formation, wound healing, and Transwell migration and invasion assays, showed that PLOD2 overexpression enhanced CRC cell proliferation, migration, and invasion, while PLOD2 silencing exerted the opposite effects. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that PLOD2 may influence CRC progression via the PI3K-AKT signaling pathway. Co-immunoprecipitation assays demonstrated that PLOD2 was co-precipitated with PI3K, confirming their interaction. Additionally, rescue experiments showed that the PI3K inhibitor LY294002 and the agonist 740Y-P could reverse PLOD2-mediated effects on CRC cell proliferation, migration, and invasion. This study demonstrates that PLOD2 promotes the proliferation, migration, and invasion of CRC cells by interacting with PI3K to activate the PI3K-AKT-GSK3β signaling pathway.

Small extracellular vesicles (SEVs) are extracellular vesicles containing DNA, RNA, and proteins and are involved in intercellular communication and function, playing an essential role in the growth and metastasis of tumors. SEVs are present in various body fluids and can be isolated and extracted from blood, urine, and cerebrospinal fluid. Under both physiological and pathological conditions, SEVs can be released by some cells, such as immune, stem, and tumor cells, in a cytosolic manner. SEVs secreted by tumor cells are called tumor-derived exosomes (TEXs) because of their origin in the corresponding parent cells. Glioma is the most common intracranial tumor, accounting for approximately half of the primary intracranial tumors, and is characterized by insidious onset, high morbidity, and high mortality rate. Complete removal of tumor tissues by surgery is difficult. Chemotherapy can improve the survival quality of patients to a certain extent; however, gliomas are prone to chemoresistance, which seriously affects the prognosis of patients. In recent years, TEXs have played a vital role in the occurrence, development, associated immune response, chemotherapy resistance, radiation therapy resistance, and metastasis of glioma. This article reviews the role of TEXs in glioma progression, drug resistance, and clinical diagnosis.

YAP/TAZ have been identified as master regulators in malignant phenotypes of glioblastoma (GBM); however, YAP/TAZ transcriptional disruptor in GBM treatment remains ineffective. Whether post‐transcriptional dysregulation of YAP/TAZ improves GBM outcome is currently unknown. Here, we report that insulin‐like growth factor 2 (IGF2) mRNA‐binding protein 1 (IGF2BP1 or IMP1) is upregulated in mesenchymal GBM compared with proneural GBM and correlates with worse patient outcome. Overexpression of IMP1 in proneural glioma stem‐like cells (GSCs) promotes while IMP1 knockdown in mesenchymal GSCs attenuates tumorigenesis and mesenchymal signatures. IMP1 binds to and stabilizes m6A‐YAP mRNA, leading to activation of YAP/TAZ signaling, depending on its m6A recognition and binding domain. On the other hand, TAZ functions as enhancer for IMP1 expression. Collectively, our data reveal a feedforward loop between IMP1 and YAP/TAZ maintaining GBM/GSC tumorigenesis and malignant progression and a promising molecular target in GBM. IMP1 is a highly expressed RNA‐binding protein in mesenchymal glioblastoma, which correlates with short survival. IMP1 binds to and stabilizes YAP m6A mRNA, leading to activation of YAP/TAZ signaling. YAP/TAZ and IMP1 form a feedforward loop, promoting stemness characteristics and mesenchymal‐like state in glioblastoma.

Ovarian cancer (OC) is a deadliest gynecological cancer with the highest mortality rate. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a crucial tumor-promoting factor, is over-expressed in several malignancies including OC. The present study aimed to explore the role and mechanisms of MTHFD2 in OC malignant progression. Thus, cell proliferation, cycling, apoptosis, migration, and invasion were evaluated by CCK-8 assay, EdU assay, flow cytometry, wound healing, transwell assay and western blotting. Additionally, glycolysis was assessed by measuring the level of glucose and lactate production, as well as the expressions of GLUT1, HK2 and PKM2. Then the expression of ferroptosis-related proteins and ERK signaling was detected using western blotting. Ferroptosis was detected through the measurement of iron level, GSH, MDA and ROS activities. The results revealed that MTHFD2 was highly expressed in OC cells. Besides, interference with MTHFD2 induced ferroptosis, promoted ROS accumulation, destroyed mitochondrial function, reduced ATP content and inhibited glycolysis in OC cells. Subsequently, we further found that interference with MTHFD2 affected mitochondrial function and glycolysis in OC cells through ERK signaling. Moreover, interference with MTHFD2 affected ferroptosis to inhibit the malignant progression of OC cells. Collectively, our present study disclosed that interference with MTHFD2 induced ferroptosis in OC to inhibit tumor malignant progression through regulating ERK signaling.