KCNK1 promotes proliferation and metastasis of breast cancer cells by activating lactate dehydrogenase A (LDHA) and up-regulating H3K18 lactylation.

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.

Role of m6A modifications in immune evasion and immunotherapy.

RNA modification has garnered increasing attention in recent years due to its pivotal role in tumorigenesis and immune surveillance. N6-methyladenosine (m6A) modification is the most prevalent RNA modification, which can affect the expression of RNA by methylating adenylate at the sixth N position to regulate the occurrence and development of tumors. Dysregulation of m6A affects the activation of cancer-promoting pathways, destroys immune cell function, maintains immunosuppressive microenvironment, and promotes tumor cell growth. In this review, we delve into the latest insights into how abnormalities in m6A modification in both tumor and immune cells orchestrate immune evasion through the activation of signaling pathways. Furthermore, we explore how dysregulated m6A modification in tumor cells influences immune cells, thereby regulating tumor immune evasion via interactions within the tumor microenvironment (TME). Lastly, we highlight recent discoveries regarding specific inhibitors of m6A modulators and the encapsulation of m6A-targeting nanomaterials for cancer therapy, discussing their potential applications in immunotherapy.

Progesterone Enhances Niraparib Efficacy in Ovarian Cancer by Promoting Palmitoleic-Acid-Mediated Ferroptosis.

Poly (adenosine 5'-diphosphate-ribose) polymerase inhibitors (PARPi) are increasingly important in the treatment of ovarian cancer. However, more than 40% of BRCA1/2-deficient patients do not respond to PARPi, and BRCA wild-type cases do not show obvious benefit. In this study, we demonstrated that progesterone acted synergistically with niraparib in ovarian cancer cells by enhancing niraparib-mediated DNA damage and death regardless of BRCA status. This synergy was validated in an ovarian cancer organoid model and in vivo experiments. Furthermore, we found that progesterone enhances the activity of niraparib in ovarian cancer through inducing ferroptosis by up-regulating palmitoleic acid and causing mitochondrial damage. In clinical cohort, it was observed that progesterone prolonged the survival of patients with ovarian cancer receiving PARPi as second-line maintenance therapy, and high progesterone receptor expression combined with low glutathione peroxidase 4 (GPX4) expression predicted better efficacy of PARPi in patients with ovarian cancer. These findings not only offer new therapeutic strategies for PARPi poor response ovarian cancer but also provide potential molecular markers for predicting the PARPi efficacy.

Immunotherapy and the ovarian cancer microenvironment: Exploring potential strategies for enhanced treatment efficacy.

Despite progress in cancer immunotherapy, ovarian cancer (OC) prognosis continues to be disappointing. Recent studies have shed light on how not just tumour cells, but also the complex tumour microenvironment, contribute to this unfavourable outcome of OC immunotherapy. The complexities of the immune microenvironment categorize OC as a 'cold tumour'. Nonetheless, understanding the precise mechanisms through which the microenvironment influences the effectiveness of OC immunotherapy remains an ongoing scientific endeavour. This review primarily aims to dissect the inherent characteristics and behaviours of diverse cells within the immune microenvironment, along with an exploration into its reprogramming and metabolic changes. It is expected that these insights will elucidate the operational dynamics of the immune microenvironment in OC and lay a theoretical groundwork for improving the efficacy of immunotherapy in OC management.

CircCDYL2 bolsters radiotherapy resistance in nasopharyngeal carcinoma by promoting RAD51 translation initiation for enhanced homologous recombination repair.

BACKGROUND: Radiation therapy stands to be one of the primary approaches in the clinical treatment of malignant tumors. Nasopharyngeal Carcinoma, a malignancy predominantly treated with radiation therapy, provides an invaluable model for investigating the mechanisms underlying radiation therapy resistance in cancer. While some reports have suggested the involvement of circRNAs in modulating resistance to radiation therapy, the underpinning mechanisms remain unclear. METHODS: RT-qPCR and in situ hybridization were used to detect the expression level of circCDYL2 in nasopharyngeal carcinoma tissue samples. The effect of circCDYL2 on radiotherapy resistance in nasopharyngeal carcinoma was demonstrated by in vitro and in vivo functional experiments. The HR-GFP reporter assay determined that circCDYL2 affected homologous recombination repair. RNA pull down, RIP, western blotting, IF, and polysome profiling assays were used to verify that circCDYL2 promoted the translation of RAD51 by binding to EIF3D protein. RESULTS: We have identified circCDYL2 as highly expressed in nasopharyngeal carcinoma tissues, and it was closely associated with poor prognosis. In vitro and in vivo experiments demonstrate that circCDYL2 plays a pivotal role in promoting radiotherapy resistance in nasopharyngeal carcinoma. Our investigation unveils a specific mechanism by which circCDYL2, acting as a scaffold molecule, recruits eukaryotic translation initiation factor 3 subunit D protein (EIF3D) to the 5'-UTR of RAD51 mRNA, a crucial component of the DNA damage repair pathway to facilitate the initiation of RAD51 translation and enhance homologous recombination repair capability, and ultimately leads to radiotherapy resistance in nasopharyngeal carcinoma. CONCLUSIONS: These findings establish a novel role of the circCDYL2/EIF3D/RAD51 axis in nasopharyngeal carcinoma radiotherapy resistance. Our work not only sheds light on the underlying molecular mechanism but also highlights the potential of circCDYL2 as a therapeutic sensitization target and a promising prognostic molecular marker for nasopharyngeal carcinoma.

Diallyl disulfide induces DNA damage and growth inhibition in colorectal cancer cells by promoting POU2F1 ubiquitination.

Previous studies have demonstrated that diallyl disulfide (DADS) exhibits potent anti-tumor activity. However, the pharmacological actions of DADS in inhibiting the growth of colorectal cancer (CRC) cells have not been clarified. Herein, we show that DADS treatment impairs the activation of the pentose phosphate pathway (PPP) to decrease PRPP (5-phosphate ribose-1-pyrophosphate) production, enhancing DNA damage and cell apoptosis, and inhibiting the growth of CRC cells. Mechanistically, DADS treatment promoted POU2F1 K48-linked ubiquitination and degradation by attenuating the PI3K/AKT signaling to up-regulate TRIM21 expression in CRC cells. Evidently, TRIM21 interacted with POU2F1, and induced the K272 ubiquitination of POU2F1. The effects of DADS on the enhanced K272 ubiquitination of POU2F1, the PPP flux, PRPP production, DNA damage and cell apoptosis as well as the growth of CRC tumors in vivo were significantly mitigated by TRIM21 silencing or activating the PI3K signaling in CRC cells. Conversely, the effects of DADS were enhanced by TRIM21 over-expression or inhibiting the PI3K/AKT signaling in CRC cells. Collectively, our findings reveal a novel mechanism by which DADS suppresses the growth of CRC by promoting POU2F1 ubiquitination, and may aid in design of novel therapeutic intervention of CRC.

The roles and molecular mechanisms of non-coding RNA in cancer metabolic reprogramming.

One of the key features of cancer is energy metabolic reprogramming which is tightly related to cancer proliferation, invasion, metastasis, and chemotherapy resistance. NcRNAs are a class of RNAs having no protein-coding potential and mainly include microRNAs, lncRNAs and circRNAs. Accumulated evidence has suggested that ncRNAs play an essential role in regulating cancer metabolic reprogramming, and the altered metabolic networks mediated by ncRNAs primarily drive carcinogenesis by regulating the expression of metabolic enzymes and transporter proteins. Importantly, accumulated research has revealed that dysregulated ncRNAs mediate metabolic reprogramming contributing to the generation of therapeutic tolerance. Elucidating the molecular mechanism of ncRNAs in cancer metabolic reprogramming can provide promising metabolism-related therapeutic targets for treatment as well as overcome therapeutic tolerance. In conclusion, this review updates the latest molecular mechanisms of ncRNAs related to cancer metabolic reprogramming.

Spatial Transcriptomic and Metabolomic Landscapes of Oral Submucous Fibrosis-Derived Oral Squamous Cell Carcinoma and its Tumor Microenvironment.

In South and Southeast Asia, the habit of chewing betel nuts is prevalent, which leads to oral submucous fibrosis (OSF). OSF is a well-established precancerous lesion, and a portion of OSF cases eventually progress to oral squamous cell carcinoma (OSCC). However, the specific molecular mechanisms underlying the malignant transformation of OSCC from OSF are poorly understood. In this study, the leading-edge techniques of Spatial Transcriptomics (ST) and Spatial Metabolomics (SM) are integrated to obtain spatial location information of cancer cells, fibroblasts, and immune cells, as well as the transcriptomic and metabolomic landscapes in OSF-derived OSCC tissues. This work reveals for the first time that some OSF-derived OSCC cells undergo partial epithelial-mesenchymal transition (pEMT) within the in situ carcinoma (ISC) region, eventually acquiring fibroblast-like phenotypes and participating in collagen deposition. Complex interactions among epithelial cells, fibroblasts, and immune cells in the tumor microenvironment are demonstrated. Most importantly, significant metabolic reprogramming in OSF-derived OSCC, including abnormal polyamine metabolism, potentially playing a pivotal role in promoting tumorigenesis and immune evasion is discovered. The ST and SM data in this study shed new light on deciphering the mechanisms of OSF-derived OSCC. The work also offers invaluable clues for the prevention and treatment of OSCC.

Cellular metabolism: A key player in cancer ferroptosis.

Cellular metabolism is the fundamental process by which cells maintain growth and self-renewal. It produces energy, furnishes raw materials, and intermediates for biomolecule synthesis, and modulates enzyme activity to sustain normal cellular functions. Cellular metabolism is the foundation of cellular life processes and plays a regulatory role in various biological functions, including programmed cell death. Ferroptosis is a recently discovered form of iron-dependent programmed cell death. The inhibition of ferroptosis plays a crucial role in tumorigenesis and tumor progression. However, the role of cellular metabolism, particularly glucose and amino acid metabolism, in cancer ferroptosis is not well understood. Here, we reviewed glucose, lipid, amino acid, iron and selenium metabolism involvement in cancer cell ferroptosis to elucidate the impact of different metabolic pathways on this process. Additionally, we provided a detailed overview of agents used to induce cancer ferroptosis. We explained that the metabolism of tumor cells plays a crucial role in maintaining intracellular redox homeostasis and that disrupting the normal metabolic processes in these cells renders them more susceptible to iron-induced cell death, resulting in enhanced tumor cell killing. The combination of ferroptosis inducers and cellular metabolism inhibitors may be a novel approach to future cancer therapy and an important strategy to advance the development of treatments.

Role of adhesion molecules in cancer and targeted therapy.

Adhesion molecules mediate cell-to-cell and cell-to-extracellular matrix interactions and transmit mechanical and chemical signals among them. Various mechanisms deregulate adhesion molecules in cancer, enabling tumor cells to proliferate without restraint, invade through tissue boundaries, escape from immune surveillance, and survive in the tumor microenvironment. Recent studies have revealed that adhesion molecules also drive angiogenesis, reshape metabolism, and are involved in stem cell self-renewal. In this review, we summarize the functions and mechanisms of adhesion molecules in cancer and the tumor microenvironment, as well as the therapeutic strategies targeting adhesion molecules. These studies have implications for furthering our understanding of adhesion molecules in cancer and providing a paradigm for exploring novel therapeutic approaches.

HPV E6/E7: insights into their regulatory role and mechanism in signaling pathways in HPV-associated tumor.

Human papillomavirus (HPV) is a class of envelope-free double-stranded DNA virus. HPV infection has been strongly associated with the development of many malignancies, such as cervical, anal and oral cancers. The viral oncoproteins E6 and E7 perform central roles on HPV-induced carcinogenic processes. During tumor development, it usually goes along with the activation of abnormal signaling pathways. E6 and E7 induces changes in cell cycle, proliferation, invasion, metastasis and other biological behaviors by affecting downstream tumor-related signaling pathways, thus promoting malignant transformation of cells and ultimately leading to tumorigenesis and progression. Here, we summarized that E6 and E7 proteins promote HPV-associated tumorigenesis and development by regulating the activation of various tumor-related signaling pathways, for example, the Wnt/ß-catenin, PI3K/Akt, and NF-kB signaling pathway. We also discussed the importance of HPV-encoded E6 and E7 and their regulated tumor-related signaling pathways for the diagnosis and effective treatment of HPV-associated tumors.

Ferritinophagy: research advance and clinical significance in cancers.

Ferritinophagy, a process involving selective autophagy of ferritin facilitated by nuclear receptor coactivator 4 (NCOA4), entails the recognition of ferritin by NCOA4 and subsequent delivery to the autophagosome. Within the autophagosome, ferritin undergoes degradation, leading to the release of iron in the lysosome. It is worth noting that excessive iron levels can trigger cell death. Recent evidence has elucidated the significant roles played by ferritinophagy and ferroptosis in regulation the initiation and progression of cancer. Given the crucial role of ferritinophagy in tumor biology, it may serve as a potential target for future anti-tumor therapeutic interventions. In this study, we have provided the distinctive features of ferritinophagy and its distinctions from ferroptosis. Moreover, we have briefly examined the fundamental regulatory mechanisms of ferritinophagy, encompassing the involvement of the specific receptor NCOA4, the Nrf2/HO-1 signaling and other pathways. Subsequently, we have synthesized the current understanding of the impact of ferritinophagy on cancer progression and its potential therapeutic applications, with a particular emphasis on the utilization of chemotherapy, nanomaterials, and immunotherapy to target the ferritinophagy pathway for anti-tumor purposes.

Roles of TRPM7 in ovarian cancer.

Ovarian cancer stands as the prevailing gynecologic malignancy, afflicting over 313,959 individuals annually worldwide, accompanied by more than 207,252 fatalities. Perturbations in calcium signaling contribute significantly to the pathogenesis of numerous cancers, including ovarian cancer, wherein alterations in calcium transporter expression have been reported. Overexpression of TRPM7, a prominent calcium transporter, has been linked to adverse prognostic outcomes in various cancer types. The focus of this comprehensive review centers around delineating the oncogenic role of TRPM7 in cancer development and exploring its therapeutic potential as a target in combating this disease. Notably, TRPM7 fosters cancer invasion, metastasis, and uncontrolled cell proliferation, thereby perpetuating the expansion and reinforcement of these malignant entities. Furthermore, this review takes ovarian cancer as an example and summarizes the "dual-mode" regulatory role of TRPM7 in cancer. Within the domain of ovarian cancer, TRPM7 assumes the role of a harsh tyrant, firmly controlling the calcium ion signaling pathway and metabolic reprogramming pathways.

Spatially Resolved Transcriptomics Technology Facilitates Cancer Research.

Single cell RNA sequencing (scRNA-seq) provides a great convenience for studying tumor occurrence and development for its ability to study gene expression at the individual cell level. However, patient-derived tumor tissues are composed of multiple types of cells including tumor cells and adjacent non-malignant cells such as stromal cells and immune cells. The spatial locations of various cells in situ tissues plays a pivotal role in the occurrence and development of tumors, which cannot be elucidated by scRNA-seq alone. Spatially resolved transcriptomics (SRT) technology emerges timely to explore the unrecognized relationship between the spatial background of a particular cell and its functions, and is increasingly used in cancer research. This review provides a systematic overview of the SRT technologies that are developed, in particular the more widely used cutting-edge SRT technologies based on next-generation sequencing (NGS). In addition, the main achievements by SRT technologies in precisely unveiling the underappreciated spatial locations on gene expression and cell function with unprecedented high-resolution in cancer research are emphasized, with the aim of developing more effective clinical therapeutics oriented to a deeper understanding of the interaction between tumor cells and surrounding non-malignant cells.

Organoids: opportunities and challenges of cancer therapy.

Organoids are a class of multicellular structures with the capability of self-organizing and the characteristic of original tissues, they are generated from stem cells in 3D culture in vitro. Organoids can mimic the occurrence and progression of original tissues and widely used in disease models in recent years. The ability of tumor organoids to retain characteristic of original tumors make them unique for tumorigenesis and cancer therapy. However, the history of organoid development and the application of organoid technology in cancer therapy are not well understood. In this paper, we reviewed the history of organoids development, the culture methods of tumor organoids establishing and the applications of organoids in cancer research for better understanding the process of tumor development and providing better strategies for cancer therapy. The standardization of organoids cultivation facilitated the large-scale production of tumor organoids. Moreover, it was found that combination of tumor organoids and other cells such as immune cells, fibroblasts and nervous cells would better mimic the microenvironment of tumor progression. This might be important developing directions for tumor organoids in the future.

Effects of altered glycolysis levels on CD8+ T cell activation and function.

CD8+ T cells are an important component of the body's adaptive immune response. During viral or intracellular bacterial infections, CD8+ T cells are rapidly activated and differentiated to exert their immune function by producing cytokines. Alterations in the glycolysis of CD8+ T cells have an important effect on their activation and function, while glycolysis is important for CD8+ T cell functional failure and recovery. This paper summarizes the importance of CD8+ T cell glycolysis in the immune system. We discuss the link between glycolysis and CD8+ T cell activation, differentiation, and proliferation, and the effect of altered glycolysis on CD8+ T cell function. In addition, potential molecular targets to enhance and restore the immune function of CD8+ T cells by affecting glycolysis and the link between glycolysis and CD8+ T cell senescence are summarized. This review provides new insights into the relationship between glycolysis and CD8+ T cell function, and proposes novel strategies for immunotherapy by targeting glycolysis.

Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential.

Metabolic reprogramming and epigenetic modifications are hallmarks of cancer cells. In cancer cells, metabolic pathway activity varies during tumorigenesis and cancer progression, indicating regulated metabolic plasticity. Metabolic changes are often closely related to epigenetic changes, such as alterations in the expression or activity of epigenetically modified enzymes, which may exert a direct or an indirect influence on cellular metabolism. Therefore, exploring the mechanisms underlying epigenetic modifications regulating the reprogramming of tumor cell metabolism is important for further understanding tumor pathogenesis. Here, we mainly focus on the latest studies on epigenetic modifications related to cancer cell metabolism regulations, including changes in glucose, lipid and amino acid metabolism in the cancer context, and then emphasize the mechanisms related to tumor cell epigenetic modifications. Specifically, we discuss the role played by DNA methylation, chromatin remodeling, noncoding RNAs and histone lactylation in tumor growth and progression. Finally, we summarize the prospects of potential cancer therapeutic strategies based on metabolic reprogramming and epigenetic changes in tumor cells.

Progesterone prevents HGSOC by promoting precancerous cell pyroptosis via inducing fibroblast paracrine.

High-grade serous ovarian carcinoma (HGSOC) is one of the most fatal gynecological cancers and has no effective prevention strategies. Herein, we demonstrated that progesterone significantly inhibited the occurrence, metastasis, and ascites of ovarian cancer in vivo, and the tumor inhibition effect of progesterone was in the tubo-ovarian intrabursal model than in the intraperitoneal or subcutaneous models. Further data demonstrated that progesterone-treated fallopian tube fibroblasts conditioned medium significantly inhibit HGSOC precancerous cell viability by inducing pyroptosis via the IL-6/ROS/NLRP3/GSDMD pathway, implying that the oviduct microenvironment may enhance progesterone's protective effects on ovarian cancer. This study elucidated progesterone inhibiting ovarian cancer mechanism and provided evidence for progesterone as a chemo-preventive role for HGSOC.

Circular RNA circRILPL1 promotes nasopharyngeal carcinoma malignant progression by activating the Hippo-YAP signaling pathway.

Circular RNAs (circRNAs) play an important regulatory role in the pathogenesis and progression of nasopharyngeal carcinoma (NPC), which have not been thoroughly elucidated. In this study, we revealed for the first time that circRILPL1 was upregulated in NPC, weakened adhesion and decreased stiffness of NPC cells, and promoted NPC proliferation and metastasis in vitro and in vivo. Mechanistically, circRILPL1 inhibited the LATS1-YAP kinase cascade by binding to and activating ROCK1, resulting in decrease of YAP phosphorylation. Binding and cooperating with transport receptor IPO7, circRILPL1 promoted the translocation of YAP from the cytoplasm to the nucleus, where YAP enhanced the transcription of cytoskeleton remodeling genes CAPN2 and PXN. By which, circRILPL1 contributed to the pathogenesis of NPC. Our results demonstrated that circRILPL1 promoted the proliferation and metastasis of NPC through activating the Hippo-YAP signaling pathway by binding to both ROCK1 and IPO7. Highly expressed circRILPL1 in NPC may serve as an important biomarker for tumor diagnosis and may also be a potential therapeutic target.