Recent advances in hematopoietic cell kinase in cancer progression: Mechanisms and inhibitors.

Hematopoietic cell kinase (Hck), a non-receptor tyrosine kinase belonging to the Src kinase family, is intricately linked to the pathogenesis of numerous human diseases, with a particularly pronounced association with cancer. Hck not only directly impacts the proliferation, migration, and apoptosis of cancer cells but also interacts with JAK/STAT, MEK/ERK, PI3K/AKT, CXCL12/CXCR4, and other pathways. Hck also influences the tumor microenvironment to facilitate the onset and progression of cancer. This paper delves into the functional role and regulatory mechanisms of Hck in various solid tumors. Additionally, it explores the implications of Hck in hematological malignancies. The review culminates with a summary of the current research status of Hck inhibitors, the majority of which are in the pre-clinical phase of investigation. Notably, these inhibitors are predominantly utilized in the therapeutic management of leukemia, with their combinatorial potential indicating promising avenues for future research. In conclusion, this review underscores the significance of the mechanism of Hck in solid tumors. This insight is crucial for comprehending the current research trends regarding Hck: targeted therapy against Hck shows great promise in both diagnosis and treatment of malignant tumors. Further investigation into the role of Hck in cancer, coupled with the development of specific inhibitors, has the potential to revolutionize approaches to cancer treatment.

METTL14/YTHDC1-Mediated m6A Modification in Hippocampus Improves Pentylenetetrazol-Induced Acute Seizures.

Epilepsy is a common neurological disorder which can cause significant morbidity and mortality. N6-methyladenosine (m6A), the most common chemical epigenetic modification among mRNA post-transcriptional modifications, implicated in various physiological and pathological processes, but its role in epilepsy is still unknown. Here, we provide strong evidences in support of an association of m6A and its regulatory proteins with epilepsy. Our results indicated that the level of m6A was declined significantly in the dentate gyrus (DG) of hippocampus of pentylenetetrazol (PTZ)-induced seizure mice. Both the seizure-like behaviors and the excessive activation of DG area neuron were significantly mitigated after the administration of m6A agonist betaine. Mechanically, we found that both the m6A methyltransferase METTL14 and recognition protein YTHDC1 were decreased by PTZ stimulation, which might contribute to the reduced m6A level. Additionally, DG-specific over-expression of METTL14 or YTHDC1 by lentivirus injection could significantly ameliorate seizure-like behaviors and prevent the excessive activation of neuron in epilepsy mice induced by PTZ injection, which might be due to the normalized m6A level. Together, this study identified that METTL14/YTHDC1-mediated m6A modification could participate in seizure-like behaviors, which might provide m6A regulation as a potential and novel therapeutic strategy for epilepsy.

Role of ferroptosis and ferroptosis-related long non'coding RNA in breast cancer.

Ferroptosis, a therapeutic strategy for tumours, is a regulated cell death characterised by the increased accumulation of iron-dependent lipid peroxides (LPO). Tumour-associated long non-coding RNAs (lncRNAs), when combined with traditional anti-cancer medicines or radiotherapy, can improve efficacy and decrease mortality in cancer. Investigating the role of ferroptosis-related lncRNAs may help strategise new therapeutic options for breast cancer (BC). Herein, we briefly discuss the genes and pathways of ferroptosis involved in iron and reactive oxygen species (ROS) metabolism, including the XC-/GSH/GPX4 system, ACSL4/LPCAT3/15-LOX and FSP1/CoQ10/NAD(P)H pathways, and investigate the correlation between ferroptosis and LncRNA in BC to determine possible biomarkers related to ferroptosis.

Metabolism of asparagine in the physiological state and cancer.

Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.

Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer.

The existing conventional treatments for breast cancer, including immune checkpoint blockade, exhibit limited effects in some cancers, particularly triple-negative breast cancer. Epigenetic alterations, specifically DNMT and HDAC alterations, are implicated in breast cancer pathogenesis. We demonstrated that DNMTs and HDACs are overexpressed and positively correlated in breast cancer. The combination of DNMT and HDAC inhibitors has shown synergistic antitumour effects, and our previously designed dual DNMT and HDAC inhibitor (termed DNMT/HDACi) 15a potently inhibits breast cancer cell proliferation, migration, and invasion and induces apoptosis in vitro and in vivo. Mechanistically, 15a induces a viral mimicry response by promoting the expression of endogenous retroviral elements in breast cancer cells, thus increasing the intracellular level of double-stranded RNA to activate the RIG-I-MAVS pathway. This in turn promotes the production of interferons and chemokines and augments the expression of interferon-stimulated genes and PD-L1. The combination of 15a and an anti-PD-L1 antibody had an additive effect in vivo. These findings indicate that this DNMT/HDACi has immunomodulatory functions and enhances the effectiveness of immune checkpoint blockade therapy. A novel dual DNMT and HDAC inhibitor induces viral mimicry, which induces the accumulation of dsRNA to activate tumoral IFN signalling and cytokine production to enhance the immune response in breast cancer.

The dePARylase NUDT16 promotes radiation resistance of cancer cells by blocking SETD3 for degradation via reversing its ADP-ribosylation.

Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.

Novel dual inhibitors of PARP and HDAC induce intratumoral STING-mediated antitumor immunity in triple-negative breast cancer.

PARP inhibitors and HDAC inhibitors have been approved for the clinical treatment of malignancies, but acquired resistance of or limited effects on solid tumors with a single agent remain as challenges. Bioinformatics analyses and a combination of experiments had demonstrated the synergistic effects of PARP and HDAC inhibitors in triple-negative breast cancer. A series of novel dual PARP and HDAC inhibitors were rationally designed and synthesized, and these molecules exhibited high enzyme inhibition activity with excellent antitumor effects in vitro and in vivo. Mechanistically, dual PARP and HDAC inhibitors induced BRCAness to restore synthetic lethality and promoted cytosolic DNA accumulation, which further activates the cGAS-STING pathway and produces proinflammatory chemokines through type I IFN-mediated JAK-STAT pathway. Moreover, these inhibitors promoted neoantigen generation, upregulated antigen presentation genes and PD-L1, and enhanced antitumor immunity when combined with immune checkpoint blockade therapy. These results indicated that novel dual PARP and HDAC inhibitors have antitumor immunomodulatory functions in triple-negative breast cancer. Novel dual PARP and HDAC inhibitors induce BRCAness to restore synthetic lethality, activating tumoral IFN signaling via the cGAS-STING pathway and inducing cytokine production, promoting neoantigen generation and presentation to enhance the immune response.

IGF2/IGF2R/Sting signaling as a therapeutic target in DSS-induced ulcerative colitis.

Ulcerative colitis is an inflammatory bowel disease with increasing prevalence and incidence. Current treatments for ulcerative colitis are not generally applicative and are often accompanied by side effects. IGF2 is an endogenous protein that plays roles in anti-inflammation and stemness maintenance, but little is known about its mechanism and function in the progression of ulcerative colitis. In this study, mouse recombinant IGF2 was used in a mouse model of ulcerative colitis established by DSS. IGF2 expression was reduced in colon tissues but not plasma of DSS-induced colitis mice. IGF2R expression was also decreased in colitis colons, which was then elevated by recombinant IGF2. Recombinant IGF2 alleviated colon injury in colitis, which was evaluated by colon shortening, body weight loss and DAI score. IGF2 treatment also relieved the inflammatory response in colitis, which was assessed by the spleen weight index, MPO activity and proinflammatory cytokine expression and was also detected in LPS-stimulated RAW264.7 cells in vitro. Moreover, IGF2R was predicted and further verified to interact with the Sting protein, and the cGAS-Sting pathway as a key pathway for stemness regulation, was upregulated in colonic colons, which was blocked by IGF2 treatment. Additionally, IGF2 treatment can maintain colonic stemness and further repair colonic tight junction function in DSS-induced colitis. In conclusion, IGF2/IGF2R downregulated the cGAS-Sting pathway to sustain colonic stemness and barrier integrity to protect against ulcerative colitis induced by DSS.

The emerging roles of metabolism in the crosstalk between breast cancer cells and tumor-associated macrophages.

Breast cancer is the most common cancer affecting women worldwide. Investigating metabolism in breast cancer may accelerate the exploitation of new therapeutic options for immunotherapies. Metabolic reprogramming can confer breast cancer cells (BCCs) with a survival advantage in the tumor microenvironment (TME) and metabolic alterations in breast cancer, and the corresponding metabolic byproducts can affect the function of tumor-associated macrophages (TAMs). Additionally, TAMs undergo metabolic reprogramming in response to signals present in the TME, which can affect their function and breast cancer progression. Here, we review the metabolic crosstalk between BCCs and TAMs in terms of glucose, lipids, amino acids, iron, and adenosine metabolism. Summaries of inhibitors that target metabolism-related processes in BCCs or TAMs within breast cancer have also served as valuable inspiration for novel therapeutic approaches in the fight against this disease. This review provides new perspectives on targeted anticancer therapies for breast cancer that combine immunity with metabolism.

CD155 and its receptors in cancer immune escape and immunotherapy.

In recent years, there have been multiple breakthroughs in cancer immunotherapy, with immune checkpoint inhibitors becoming the most promising treatment strategy. However, available drugs are not always effective. As an emerging immune checkpoint molecule, CD155 has become an important target for immunotherapy. This review describes the structure and function of CD155, its receptors TIGIT, CD96, and CD226, and summarizes that CD155 expressed by tumor cells can upregulate its expression through the DNA damage response pathway and Ras-Raf-MEK-ERK signaling pathway. This review also elaborates the mechanism of immune escape after binding CD155 to its receptors TIGIT, CD96, and CD226, and summarizes the current progress of immunotherapy research regarding CD155 and its receptors. Besides, it also discusses the future direction of checkpoint immunotherapy.

Downregulated circPOKE promotes breast cancer metastasis through activation of the USP10-Snail axis.

Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer-related death among females. Metastasis accounts for the majority of BC related deaths. One feasible strategy to solve this challenging problem is to disrupt the capabilities required for tumor metastasis. Herein, we verified a novel metastasis suppressive circRNA, circPOKE in BC. circPOKE was downregulated in primary and metastatic BC tissues and overexpression of circPOKE inhibited the metastatic potential but not the proliferative ability of BC cells in vitro and in vivo. Mechanistically, circPOKE competitively binds to USP10, and reduces its binding to Snail, a key transcriptional regulator of EMT, thereby inhibiting Snail stability via the protein-ubiquitination degradation pathway. In addition, we found that circPOKE could be secreted into the extracellular space via exosomes and that exosome-carried circPOKE significantly inhibited the invasive capabilities of BC cells in vitro and in vivo. Furthermore, the levels of circPOKE, USP10 and Snail are clinically relevant in BC, suggesting that circPOKE may be used as a potential therapeutic target for patients with BC metastasis.

FUNDC2, a mitochondrial outer membrane protein, mediates triple-negative breast cancer progression via the AKT/GSK3ß/GLI1 pathway.

Triple-negative breast cancer (TNBC) lacks effective therapeutic targets and has a poor prognosis, easy recurrence and metastasis. It is urgent and important to explore TNBC treatment targets. Through mass spectrometry combined with qRT-PCR validation in luminal A cells and TNBC cells, high-content screening and clinical sample analysis, FUNDC2 was discovered as a novel target. The function of the outer mitochondrial membrane protein FUNDC2 in breast cancer is still unclear. In this study, we find that FUNDC2 expression in TNBC tissues is significantly higher than that in luminal subtype breast cancer tissues. FUNDC2 silencing in TNBC cells significantly reduces cell proliferation, migration and invasion. As demonstrated in vivo using subcutaneous tumor xenografts in mice, FUNDC2 suppression significantly inhibits tumor growth. The underlying mechanism might be mediated by inactivating its downstream signal AKT/GSK3ß and GLI1, a key factor of the Hedgehog signaling pathway. Therefore, FUNDC2 may promote TNBC progression and provide a therapeutic target for treating TNBC.

Lipid Metabolic Regulatory Crosstalk Between Cancer Cells and Tumor-Associated Macrophages.

In the tumor microenvironment, tumor-associated macrophages (TAMs) are one of the most abundant cell populations, playing key roles in tumorigenesis, chemoresistance, immune evasion, and metastasis. There is an important interaction between TAMs and cancer cells: on the one hand, tumors control the function of infiltrating macrophages, contributing to reprogramming of TAMs, and on the other hand, TAMs affect the growth of cancer cells. This review focuses on lipid metabolism changes in the complex relationship between cancer cells and TAMs. We discuss how lipid metabolism in cancer cells affects macrophage phenotypic and metabolic changes and, subsequently, how altered lipid metabolism of TAMs influences tumor progression. Identifying the metabolic changes that influence the complex interaction between tumor cells and TAMs is also an important step in exploring new therapeutic approaches that target metabolic reprogramming of immune cells to enhance their tumoricidal potential and bypass therapy resistance. Our work may provide new targets for antitumor therapies.

Mechanisms of NAT10 as ac4C writer in diseases.

In the early stage, N4-acetylcytidine (ac4C) was regarded as a conservative nucleoside present on tRNA and rRNA. Recently, studies have shown that ac4C also exists in human and yeast mRNA. N-Acetyltransferase-like protein 10 (NAT10) is the first enzyme to be found to catalyze ac4C production in eukaryotic RNA and has acetyltransferase activity and RNA-binding activity. Here, we first describe the structure and cellular localization of NAT10. Then, we conclude the active roles of NAT10 as the ac4C "writer" in mRNA stability and translation efficiency, oocyte maturation, bone remodeling, and fatty acid metabolism. With respect to disease, we focused on the promoting functions of NAT10 in proliferation, metastasis, and apoptosis in multiple tumors. The immune regulatory role of NAT10 in systemic lupus erythematosus and the maintenance role of NAT10 in virus RNA stability and replication in influenza A virus are also introduced. This review identifies NAT10 as a potential target for diagnosis, therapy, and prognosis in clinical application.

Intracellular FGF1 promotes invasion and migration in thyroid carcinoma via HMGA1 independent of FGF receptors.

Background: Fibroblast growth factor 1 (FGF1) is extensively amplified in many tumors and accelerates tumor invasion and metastasis. However, the role and precise molecular mechanism by which FGF1 participates in thyroid cancer (TC) are still unclear. Methods: Quantitative real-time polymerase chain reaction- and western blotting were used to detect the mRNA and protein levels of FGF1, high mobility group A (HMGA1), epithelial-to-mesenchymal transition (EMT)-related factors, and FGFs in both TC tissues and cell lines. Immunohistochemistry was conducted to examine the expression of FGF1 and HMGA1. Immunofluorescence staining was used to detect the coexpression of FGF1 and HMGA1. Transwell and wound healing assays were conducted to evaluate the effects of FGF1 on the capacity of invasion and migration in cells. Results: FGF1 was upregulated in papillary thyroid carcinoma (PTC) tissues and cell lines and was relatively higher in PTC tissues with cervical lymph node metastasis. Furthermore, FGF1 promotes invasion and metastasis through the EMT pathway. Mechanistically, FGF1 promotes EMT through intracellular function independent of FGF receptors. Interestingly, we demonstrated that FGF1 could upregulate HMGA1 in TC cells, and the correlation of FGF1 and HMGA1 was positive in PTC tissues. FGF1 and HMGA1 had obvious colocalization in the nucleus. We further revealed that FGF1 promotes the invasion and migration of TC cells through the upregulation of HMGA1. Conclusion: Intracellular FGF1 could promote invasion and migration in TC by mediating the expression of HMGA1 independent of FGF receptors, and FGF1 may be an effective therapeutic target in TC.

Mitochondrial Stress in Metabolic Inflammation: Modest Benefits and Full Losses.

Energy intake and metabolic balance are the pillars of health preservation. Overnutrition causes nonspecific, persistently low inflammatory state known as metabolic inflammation. This condition contributes to the pathophysiology of various metabolic disorders, such as atherosclerosis, obesity, diabetes mellitus, and metabolic syndrome. The mitochondria maintain the balance of energy metabolism. Excessive energy stress can lead to mitochondrial dysfunction, which promotes metabolic inflammation. The inflammatory environment further impairs mitochondrial function. Accordingly, excellent organism design keeps the body metabolically healthy in the context of mitochondrial dysfunction, and moderate mitochondrial stress can have a beneficial effect. This review summarises the research progress on the multifaceted characterisation of mitochondrial dysfunction and its role in metabolic inflammation.

Non-coding RNAs in breast cancer: Implications for programmed cell death.

Cell death is a necessary event in life and is crucial for the regulation of organismal development, homeostasis, aging and pathological conditions. There are different modes of cell death, i.e., regulated and nonregulated. Cell death induced by programmed cell death (PCD) has gained increasing attention in recent years. Abnormal control of PCD plays an important role in tumorigenesis. For example, tumor cells are relatively resistant to apoptosis, and the induction of cell death is also an important mechanism underlying the antitumor effects of current clinical chemotherapeutic agents. Recently, studies have revealed that noncoding RNAs (ncRNAs) are involved in regulating multiple biological processes of breast cancer, including PCD. NcRNAs can exert both protumorigenic and antitumorigenic effects, depending on their expression patterns. Therefore, constructing ncRNA-based therapies to target PCD may be a promising therapeutic strategy for breast cancer. Herein, this review discusses the function of various ncRNAs in regulating the PCD of breast cancer cells. In addition, given the recent trend of utilizing ncRNAs as cancer therapeutics, we also discuss the great potential applications of ncRNAs as biomarkers or activators of PCD in breast cancer.

Inhibitory effect of the novel tyrosine kinase inhibitor DCC-2036 on triple-negative breast cancer stem cells through AXL-KLF5 positive feedback loop.

Triple-negative breast cancer (TNBC), an aggressive histological subtype of breast cancer, exhibits a high risk of early recurrence rate and a poor prognosis, and it is primarily associated with the abundance of cancer stem cells (CSCs). At present, the strategies for effectively eradicating or inhibiting TNBC CSCs are still limited, which makes the development of novel drugs with anti-CSCs function be of great value for the treatment of TNBC, especially the refractory TNBC. In this study, we found that the small-molecule tyrosine kinase inhibitor DCC-2036 suppressed TNBC stem cells by inhibiting the tyrosine kinase AXL and the transcription factor KLF5. DCC-2036 downregulated the expression of KLF5 by decreasing the protein stability of KLF5 via the AXL-Akt-GSK3ß signal axis, and in turn, the downregulation of KLF5 further reduced the expression of AXL via binding to its promotor (-171 to -162 bp). In addition, p-AXL/AXL levels were positively correlated with KLF5 expression in human TNBC specimens. These findings indicated that DCC-2036 is able to suppress the CSCs in TNBC by targeting the AXL-KLF5 positive feedback loop. Moreover, our findings indicated that DCC-2036 increased the sensitivity of TNBC chemotherapy. Therefore, this study proposes a potential drug candidate and several targets for the treatment of refractory TNBC.

Extracellular vesicle miR-32 derived from macrophage promotes arterial calcification in mice with type 2 diabetes via inhibiting VSMC autophagy.

BACKGROUND: The development of diabetes vascular calcification (VC) is tightly associated with the inhibition of vascular smooth muscle cell (VSMC) autophagy. Previously, our team found that miR-32-5p (miR-32) promotes macrophage activation, and miR-32 is expressed at higher level in the plasma of patients with coronary calcification. However, whether miR-32 mediates the function of macrophages in type 2 diabetes (T2D) VC is still unclear. METHODS: Wild-type (WT) and miR-32-/- mice were used in this study. qRT-PCR and western blotting were used to analyze gene expression. Flow cytometry was used to analyze the influence of glucose concentration on macrophage polarization. Nanoparticle tracking analysis (NTA), transmission electron microscopy, and confocal microscopy were used to identify macrophage extracellular vehicles (EVs). Immunofluorescence, in situ hybridization (ISH), immunohistochemistry, and alizarin red staining were used to analyze the influence of macrophage EVs on autophagy and calcification of the aorta of miR-32-/- mice. A luciferase assay was used to analyze the effect of miR-32 on myocyte enhancer factor 2D (Mef2d) expression. Co-IP combined with mass spectrometry (MS) and transcriptome sequencing was used to analyze the signalling pathway by which Mef2d acts in VSMC autophagy. RESULTS: We found that high glucose conditions upregulate miR-32 expression in macrophages and their EVs. Importantly, macrophages and their EVs promote VSMC osteogenic differentiation and upregulate miR-32 expression in VSMCs. Moreover, miR-32 mimics transfection promoted osteogenic differentiation and inhibited autophagy in VSMCs. In vitro and in vivo experiments showed that Mef2d is the key target gene of miR-32 that inhibits VSMC autophagy. Furthermore, MS and transcriptome sequencing found that cGMP-PKG is an important signalling pathway by which Mef2d regulates VSMC autophagy. In addition, after T2D miR-32-/- mice were injected with macrophage EVs via the caudal vein, miR-32 was detected in aortic VSMCs of miR-32-/- mice. Moreover, autophagy was significantly inhibited, and calcification was significantly enhanced in aorta cells. CONCLUSIONS: These results reveal that EVs are the key pathway by which macrophages promote T2D VC, and that EVs miR-32 is a key cause of autophagy inhibition in VSMCs.