Facts and prospects of peptide in targeted therapy and immune regulation against triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Due to the lack of specific therapeutic targets, treatment options are limited, and the recurrence and metastasis rate is high, the overall survival of patients is poor. However, with the discovery of some new targets and the corresponding immune regulation after targeting these targets, TNBC has a new hope in treatment. The peptide has a simple structure, strong binding affinity, and high stability, and has great potential in targeted therapy and immune regulation against TNBC. This review will discuss how single peptides and peptide combinations target triple-negative breast cancer to exert immunomodulatory effects. Among them, single peptides target specific receptors on TNBC cells, act as decoys to target key ligands in the regulatory pathway, and target TME-related cells. The combinations of peptides work in the form of cancer vaccines, engineered exosomes, microRNAs and other immune-related molecular pathways, immune checkpoint inhibitors, chimeric antigen receptor T cells, and drug-peptide conjugates. This article is mainly dedicated to exploring new treatment methods for TNBC to improve the curative effect and prolong the survival time of patients.

The role of peptides in reversing chemoresistance of breast cancer: current facts and future prospects.

Breast cancer is the first malignant tumor in women, and its incidence is also increasing year by year. Chemotherapy is one of the standard therapies for breast cancer, but the resistance of breast cancer cells to chemotherapy drugs is a huge challenge for the effective treatment of breast cancer. At present, in the study of reversing the drug resistance of solid tumors such as breast cancer, peptides have the advantages of high selectivity, high tissue penetration, and good biocompatibility. Some of the peptides that have been studied can overcome the resistance of tumor cells to chemotherapeutic drugs in the experiment, and effectively control the growth and metastasis of breast cancer cells. Here, we describe the mechanism of different peptides in reversing breast cancer resistance, including promoting cancer cell apoptosis; promoting non-apoptotic regulatory cell death of cancer cells; inhibiting the DNA repair mechanism of cancer cells; improving the tumor microenvironment; inhibiting drug efflux mechanism; and enhancing drug uptake. This review focuses on the different mechanisms of peptides in reversing breast cancer drug resistance, and these peptides are also expected to create clinical breakthroughs in promoting the therapeutic effect of chemotherapy drugs in breast cancer patients and improving the survival rate of patients.

LAPTM4B promotes AML progression through regulating RPS9/STAT3 axis.

Acute myeloid leukemia (AML) is a heterogeneous disorder with high morbidity and mortality under the existing treatment strategy. Here, we found that lysosome-associated protein transmembrane 4 beta (LAPTM4B) was frequently upregulated in AML, and high LAPTM4B was associated with poor outcome. Moreover, LAPTM4B promoted leukemia progression in vitro and in vivo. Mechanically, LAPTM4B interacted with RPS9, and positively regulated RPS9 protein stability, which enhanced leukemia cell progression via activating STAT3. Our findings indicate for the first time that LAPTM4B contributes to leukemia progression in a RPS9/STAT3-dependent manner, suggesting that LAPTM4B may serve as a promising target for treatment of AML.

Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis.

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2+ACE2+ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2+ACE2+ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27+ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2+ACE2+ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2+ACE2+ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

Targeting Mitochondrial Oxidative Phosphorylation Eradicates Acute Myeloid Leukemic Stem Cells.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by multiple cytogenetic and molecular abnormalities, with a very poor prognosis. Current treatments for AML often fail to eliminate leukemic stem cells (LSCs), which perpetuate the disease. LSCs exhibit a unique metabolic profile, especially dependent on oxidative phosphorylation (OXPHOS) for energy production. Whereas, normal hematopoietic stem cells (HSCs) and leukemic blasts rely on glycolysis for adenosine triphosphate (ATP) production. Thus, understanding the regulation of OXPHOS in LSCs may offer effective targets for developing clinical therapies in AML. This review summarizes these studies with a focus on the regulation of the electron transport chain (ETC) and tricarboxylic acid (TCA) cycle in OXPHOS and discusses potential therapies for eliminating LSCs.

[Effect of Laptm4b Deletion on Hematopoietic Stem and Progenitor Cells Homeostasis in Mice].

OBJECTIVE: To investigate the effect of lysosomal-associated protein transmembrane-4 Beta(Laptm4b) deletion on hematopoietic stem/progenitor cells (HSPCs) homeostasis in mice. METHODS: The hematopoietic system specific Laptm4b-deficient mice were constructed. The number and proportion of HSPCs (LSK, LT, ST, MPP, etc) in Laptm4b-deficient mice were analyzed by flow cytometry. Single SLAM-HSC cell was sorted by flow sorter and cultured in vitro to measure the effect of Laptm4b deletion on the colony forming ability of hematopoietic stem cells (HSCs). The effect of Laptm4b-deficient on the reconstitution ability of HSCs in mice was detected by competitive transplantation experiment of SLAM-HSC cells. RESULTS: Laptm4b deficiency could moderately upregulate the proportion of T cells in the peripheral blood of the mice, but showed no significant effect on the proportion and number of HSPCs. Laptm4b deletion showed no effect on the reconstruction ability of HSCs after competitive transplantation, but it could inhibit the colony formation of HSCs in vitro. CONCLUSION: LAPTM4B may play a role in HSCs under the proliferation stress. Laptm4b-deficient in mice hematopoietic system showed no significant effect on the HSPCs homeostasis maintenance and reconstruction ability.

Prognostic Significance of CD56 Antigen Expression in Patients with De Novo Non-M3 Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous group of disorders with distinct characteristics and prognoses. Although cytogenetic changes and gene mutations are associated with AML prognosis, there is a need to identify further factors. CD56 is considered a prognostic factor for AML, which is abnormally expressed in leukemia cells. However, a clear consensus for this surface molecule is lacking, which has prompted us to investigate its prognostic significance. Bone marrow samples of de novo non-M3 AML were collected to detect CD56 expression using multiparameter flow cytometry (FCM). As a result, the CD56 expression in de novo non-M3 AML was found to be significantly higher than that in acute lymphoma leukemia (ALL, P = 0.017) and healthy controls (P = 0.02). The X-Tile program produced a CD56 cutoff point at a relative expression level of 24.62%. Based on this cutoff point, high CD56 expression was observed in 29.21% of de novo non-M3 AML patients. CD56-high patients had a poor overall survival (OS, P = 0.015) compared to CD56-low patients. Bone marrow transplantation (BMT) improved OS (P = 0.004), but a poor genetic risk was associated with an inferior OS (P = 0.002). Compared with CD56-low patients, CD56-high patients had lower peripheral blood platelet (PLT) counts (P = 0.010). Our research confirmed that high CD56 expression is associated with adverse clinical outcomes in de novo non-M3 AML patients, indicating that CD56 could be used as a prognostic marker for a more precise stratification of de novo non-M3 AML patients.

Nuclear DEK preserves hematopoietic stem cells potential via NCoR1/HDAC3-Akt1/2-mTOR axis.

The oncogene DEK is found fused with the NUP214 gene creating oncoprotein DEK-NUP214 that induces acute myeloid leukemia (AML) in patients, and secreted DEK protein functions as a hematopoietic cytokine to regulate hematopoiesis; however, the intrinsic role of nuclear DEK in hematopoietic stem cells (HSCs) remains largely unknown. Here, we show that HSCs lacking DEK display defects in long-term self-renew capacity, eventually resulting in impaired hematopoiesis. DEK deficiency reduces quiescence and accelerates mitochondrial metabolism in HSCs, in part, dependent upon activating mTOR signaling. At the molecular level, DEK recruits the corepressor NCoR1 to repress acetylation of histone 3 at lysine 27 (H3K27ac) and restricts the chromatin accessibility of HSCs, governing the expression of quiescence-associated genes (e.g., Akt1/2, Ccnb2, and p21). Inhibition of mTOR activity largely restores the maintenance and potential of Dek-cKO HSCs. These findings highlight the crucial role of nuclear DEK in preserving HSC potential, uncovering a new link between chromatin remodelers and HSC homeostasis, and have clinical implications.

Zfp521 is essential for the quiescence and maintenance of adult hematopoietic stem cells under stress.

Zinc finger protein 521 (Zfp521), a quiescent hematopoietic stem cell (HSC)-enriched transcription factor, is involved in the self-renewal and differentiation of fetal liver HSC. However, its role in adult hematopoiesis remains elusive. Here, we found that Zfp521 deletion did not inhibit adult hematopoiesis under homeostatic conditions. In contrast, Zfp521-null chimeric mice showed significantly reduced pool size of HSC and hematopoietic progenitor cells associated with increased apoptosis and loss of quiescence. Competitive serial transplantation assays revealed that Zfp521 regulates HSC self-renewal and differentiation under regenerative stress. Mechanistically, Zfp521 transcriptionally repressed Rela expression by increasing H3K9ac and decreasing H3K9me3 levels in its promoter. Knockdown of Rela inhibited the hyper-activated NF-κB pathway and reversed the loss of quiescence in Zfp521-null HSC under stress. Thus, our results reveal a previously unrecognized role for Zfp521 as critical regulator of quiescence and self-renewal of HSC in adult hematopoiesis mediated at least partly by controlling Rela expression.

A single copy of large tumor suppressor 1 or large tumor suppressor 2 is sufficient for normal hematopoiesis.

BACKGROUND: Hematopoietic stem cells (HSCs) have the ability to differentiate into all subsets of blood cells and self-renew. Large tumor suppressor 1 (LATS1) and large tumor suppressor 2 (LATS2) kinases are essential for cell cycle regulation, organism fitness, genome integrity, and cancer prevention. Here, we investigated whether Lats1 and Lats2 are critical for the maintenance of the self-renewal and quiescence capacities of HSCs in mice. METHODS: Quantitative reverse transcription-polymerase chain reaction was used to determine the expression levels of Lats1 and Lats2 in subsets of progenitor cells and mature bone marrow cells. A clustered regularly interspaced short palindromic repeats system was used to generate Lats1 or Lats2 knockout mice. Complete blood cell counts were used to compare the absolute number of white blood cells, lymphocytes, monocytes, neutrophils, and platelets between Lats1 or Lats2 heterozygotes and littermates. Flow cytometry was used to assess the size of hematopoietic progenitor cells (HPCs) and HSC pools in Lats1 or Lats2 heterozygotes and littermates. The comparison between the two groups was analyzed using Student's t test. RESULTS: Lats1 and Lats2 were widely expressed in hematopoietic cells with higher expression levels in primitive hematopoietic cells than in mature cells. Lats1 or Lats2 knockout mice were generated, with the homozygotes showing embryonic lethality. The size of the HPC and HSC pools in Lats1 (HPC: wild-type [WT] vs. heterozygote, 220,426.77 ±â€Š54,384.796 vs. 221,149.4 ±â€Š42,688.29, P = 0.988; HSC: WT vs. heterozygote, 2498.932 ±â€Š347.856 vs. 3249.763 ±â€Š370.412, P = 0.105) or Lats2 (HPC: WT vs. heterozygote, 425,540.52 ±â€Š99,721.86 vs. 467,127.8 ±â€Š89,574.48, P = 0.527; HSC: WT vs. heterozygote, 4760.545 ±â€Š1518.01 vs. 5327.437 ±â€Š873.297, P = 0.502) heterozygotes were not impaired. Moreover, the depletion of Lats1 or Lats2 did not affect the overall survival of the heterozygotes (Lats1: P = 0.654; Lats2: P = 0.152). CONCLUSION: These results indicate that a single allele of Lats1 or Lats2 may be sufficient for normal hematopoiesis.

Zinc finger and BTB domain-containing protein 46 is essential for survival and proliferation of acute myeloid leukemia cell line but dispensable for normal hematopoiesis.

BACKGROUND: Zinc finger and BTB domain-containing protein 46 (Zbtb46) is a transcription factor identified in classical dendritic cells, and maintains dendritic cell quiescence in a steady state. Zbtb46 has been reported to be a negative indicator of acute myeloid leukemia (AML). We found that Zbtb46 was expressed at a relatively higher level in hematopoietic stem and progenitor cells (HSPCs) compared to mature cells, and higher in AML cells compared to normal bone marrow (BM) cells. However, the role of Zbtb46 in HSPCs and AML cells remains unclear. Therefore, we sought to elucidate the effect of Zbtb46 in normal hematopoiesis and AML cells. METHODS: We generated Zbtb46 and Zbtb46Mx1-Cre mice. The deletion of Zbtb46 in Zbtb46Mx1-Cre mice was induced by intraperitoneal injection of double-stranded poly (I). poly (C) (poly(I:C)), and referred as Zbtb46 cKO. After confirming the deletion of Zbtb46, the frequency and numbers of HSPCs and mature blood cells were analyzed by flow cytometry. Serial intraperitoneal injection of 5-fluorouracil was administrated to determine the repopulation ability of HSCs from Zbtb46 and Zbtb46 cKO mice. The correlation between Zbtb46 expression and prognosis was analyzed using the data from the Cancer Genome Atlas. To investigate the role of Zbtb46 in AML cells, we knocked down the expression of Zbtb46 in THP-1 cells using lentiviral vectors expressing small hairpin RNAs targeting Zbtb46. Cell proliferation rate was determined by cell count assay. Cell apoptosis and bromodeoxyuridine incorporation were determined by flow cytometry. RESULTS: The percentages and absolute numbers of HSPCs and mature blood cells were comparable in Zbtb46 cKO mice and its Zbtb46 littermates (Zbtb46vs. Zbtb46 cKO, HPC: 801,310 ±â€Š84,282 vs. 907,202 ±â€Š97,403, t = 0.82, P = 0.46; LSK: 86,895 ±â€Š7802 vs. 102,210 ±â€Š5025, t = 1.65, P = 0.17; HSC: 19,753 ±â€Š3116 vs. 17,608 ±â€Š3508, t = 0.46, P = 0.67). The repopulation ability of HSCs from Zbtb46Mx1-Cre mice was similar to those from Zbtb46 control (P = 0.26). Zbtb46 had elevated expression in AML cells compared to total BM cells from normal control. Knockdown of Zbtb46 in THP-1 cells led to a significant increase in cell apoptosis and reduced cell growth and proliferation. CONCLUSION: Collectively, our data indicate that Zbtb46 is essential for survival and proliferation of AML cells, but dispensable for normal hematopoiesis.

Exercise protects proliferative muscle satellite cells against exhaustion via the Igfbp7-Akt-mTOR axis.

Background and Purpose: The exhaustion of muscle satellite cells (SCs) is correlated with muscle diseases, including sarcopenia and Duchenne muscular dystrophy. Exercise benefits skeletal muscle homeostasis and promotes proliferation of SCs. Elucidating the molecular mechanism underlying the muscle function-improving effect of exercise has important implications in regenerative medicine. Methods: Herein, we investigated the effect of 4-week treadmill training on skeletal muscle and SCs in mice. Hematoxylin and eosin (HE) staining was utilized to detect the morphometry of skeletal muscles. Flow cytometry and immunofluorescence were conducted to analyze the abundance and cell cycle of SCs. RNA sequencing was performed to elucidate the transcriptional regulatory network of SCs. The ChIP-PCR assay was used to detect enrichment of H3K27ac at the promoters of Akt. Results: We observed that exercise resulted in muscle hypertrophy and improved muscle regeneration in mice. Unexpectedly, exercise promoted cell cycling but suppressed the Akt-mTOR pathway in SCs. Proliferative SCs in "exercised mice" required suppressed mTOR activity to limit mitochondrial metabolism, maintaining the "limited activation status" of SCs against exhaustion. Mechanistically, exercise upregulated the expression of Igfbp7, thereby impeding the phosphorylation of Akt and resulting in inhibited mTOR activity and limited mitochondrial metabolism. The limited mitochondrial metabolism resulted in hypoacetylation of histone 3 and reduced enrichment of H3K27ac at promoters of Akt, decreasing the transcription of Akt. Moreover, repeatedly injured mice showed a preserved SC pool and improved muscle regeneration by the suppression of Akt-mTOR signaling. Conclusions: The findings of our study show that exercise protects proliferative SCs against exhaustion via the Igfbp7-Akt-mTOR axis. These findings establish a link between mechanical signaling, mitochondrial metabolism, epigenetic modification, and stem cell fate decisions; thus, present potential therapeutic targets for muscle diseases correlated with SC exhaustion.

A Cdh1-FoxM1-Apc axis controls muscle development and regeneration.

Forkhead box M1 (FoxM1) transcriptional factor has a principal role in regulating cell proliferation, self-renewal, and tumorigenesis. However, whether FoxM1 regulates endogenous muscle development and regeneration remains unclear. Here we found that loss of FoxM1 in muscle satellite cells (SCs) resulted in muscle atrophy and defective muscle regeneration. FoxM1 functioned as a direct transcription activator of adenomatous polyposis coli (Apc), preventing hyperactivation of wnt/ß-catenin signaling during muscle regeneration. FoxM1 overexpression in SCs promoted myogenesis but impaired muscle regeneration as a result of spontaneous activation and exhaustion of SCs by transcriptional regulation of Cyclin B1 (Ccnb1). The E3 ubiquitin ligase Cdh1 (also termed Fzr1) was required for FoxM1 ubiquitylation and subsequent degradation. Loss of Cdh1 promoted quiescent SCs to enter into the cell cycle and the SC pool was depleted by serial muscle injuries. Haploinsufficiency of FoxM1 ameliorated muscle regeneration of Cdh1 knock-out mice. These data demonstrate that the Cdh1-FoxM1-Apc axis functions as a key regulator of muscle development and regeneration.

Zfp521 SUMOylation facilities erythroid hematopoietic reconstitution under stress.

Zinc finger protein 521 (Zfp521) is a key transcriptional factor in regulation of hematopoiesis. SUMOylation, a protein post-translational modification process, plays important roles in various biological process including hematopoiesis. However, whether Zfp521 can be SUMOylated and how it affects hematopoiesis is unknown. In this study, we confirmed that Zfp521 can be modified by SUMO1 and lysine 1146 was the primary SUMOylation site. Under homeostatic condition, Zfp521 SUMOylation-deficient mice had normal mature blood cells and primitive cells. However, in bone marrow (BM) transplantation assay, recipient mice transplanted with BM cells from Zfp521 SUMOylation-deficient mice had a significantly decreased R2 population of erythroid lineage in BM and spleen compared with those transplanted with BM cells from wild-type mice. Our results found a novel function of Zfp521 SUMOylation in erythroid reconstitution under stress, which might be a new therapeutic target in future.

Resveratrol: Review on its discovery, anti-leukemia effects and pharmacokinetics.

Resveratrol, found in variety of plants, is a natural stilbene structure polyphenol. It has various pharmacological effects, such as antioxidation, anti-aging, anti-inflammation, anti-cancer, antiobesity, anti-diabetes, cardioprotection, neuroprotection. Recently, anti-leukemia activities of resveratrol has been studied extensively via its effects on a variety of biological processes involving cell proliferation, apoptosis, autophagy. Current treatments of leukemia mainly rely on intensive chemotherapy or hematopoietic stem cell transplantation, however, these treatments are still with poor survival and high treatment-related mortality. Therefore, it is extremely needed to find relatively non-toxic medicines with minimal side effects but sufficient therapeutic efficacy. Resveratrol is one such potential candidate owing to its reported anti-leukemia effect. In this review, we summarized resveratrol's discovery, sources and isolation methods, administration methods, effects in different types of leukemia, pharmacokinetics and toxicities, aiming to exploit resveratrol as a potential drug candidate for anti-leukemia.