UNASSIGNED: Rising cancer-related mortality underscores the importance of biomarkers for treatment and prognosis, with Chromosome Segregation 1 Like (CSE1L) linked to various cancers yet its roles remain partially understood. This study investigates CSE1L\'s expression and oncogenic mechanisms in solid tumors.
UNASSIGNED: We analyzed multi-omics data from 31 solid tumors, measured CSE1L in 41 head and neck carcinoma patients post-chemotherapy via qRT-PCR, and evaluated the impact of CSE1L knockdown on cell proliferation in A549 and HepG2 cells.
UNASSIGNED: In this study, we observed significantly elevated levels of CSE1L RNA in 13 tumor tissues and protein levels in 8 tumor tissues compared to their corresponding adjacent normal tissues. Additionally, our investigation unveiled a correlation between heightened CSE1L expression in tumor tissues and worsened patient prognosis, poor response to immunotherapy, and diminished effectiveness of neoadjuvant chemotherapy. Through an analysis of CSE1L mechanisms, we discovered its potential involvement in promoting tumor cell proliferation, enhancing drug resistance, and influencing immune infiltration, thereby impacting patient prognosis and treatment outcomes. Finally, we delved into the potential mechanisms underlying upregulation of CSE1L in tumor tissues.
UNASSIGNED: Our findings demonstrate that CSE1L promotes tumor development in various malignancies, highlighting its potential as both a therapeutic target and prognostic indicator.

UNASSIGNED: DEAD-box helicase 27 (DDX27), a member of the DEAD-Box nucleic acid helicase family, holds an elusive role in oral squamous cell carcinoma (OSCC). This study aims to unravel the regulatory functions of DDX27 in OSCC and explore its downstream targets.
METHODS: A commercial oral squamous cell carcinoma (OSCC) tissue microarray (TMA) was utilized. We analyzed differentially expressed genes in OSCC through the GEO database. Target gene silencing was achieved using the shRNA-mediated lentivirus method. Coexpedia analysis identified co-expressed genes associated with DDX27. Additionally, a Co-Immunoprecipitation (Co-IP) experiment confirmed the protein interaction between DDX27 and CSE1L. Xenograft tumor models were employed to evaluate DDX27\'s role in OSCC tumor formation.
RESULTS: Elevated DDX27 expression in OSCC correlated with a higher pathological grade. DDX27 knockdown resulted in decreased cell proliferation, increased apoptosis, inhibited cell migration, and induced G2/M phase cell cycle arrest, as well as impaired tumor outgrowth. Coexpedia analysis identified STAU1, NELFCD, and CSE1L as top co-expressed genes. Lentiviral vectors targeting STAU1, NELFCD, and CSE1L revealed that silencing CSE1L significantly impaired cell growth, indicating it as a downstream target of DDX27. Cell rescue experiments demonstrated that increased DDX27 levels ameliorated cell proliferation, attenuated apoptosis, and CSE1L depletion blocked cell development induced by DDX27 overexpression.
CONCLUSIONS: This study highlighted DDX27 as a potential therapeutic target for OSCC treatment, shedding light on its crucial role in OSCC development. Targeting DDX27 or its downstream effector, CSE1L, holds promise for innovative OSCC therapies.

Exportin receptors are concentrated in the nucleus to transport essential cargoes out of it. A mislocalization of exportins to the cytoplasm is linked to disease. Hence, it is important to understand how their containment within the nucleus is regulated. Here, we have studied the nuclear efflux of exportin2 (cellular apoptosis susceptibility protein or CAS) that delivers karyopherinα (Kapα or importinα), the cargo adaptor for karyopherinβ1 (Kapβ1 or importinβ1), to the cytoplasm in a Ran guanosine triphosphate (RanGTP)-mediated manner. We show that the N-terminus of CAS attenuates the interaction of RanGTPase activating protein 1 (RanGAP1) with RanGTP to slow GTP hydrolysis, which suppresses CAS nuclear exit at nuclear pore complexes (NPCs). Strikingly, a single phosphomimetic mutation (T18D) at the CAS N-terminus is sufficient to abolish its nuclear retention and coincides with metastatic cellular behavior. Furthermore, downregulating Kapβ1 disrupts CAS nuclear retention, which highlights the balance between their respective functions that is essential for maintaining the Kapα transport cycle. Therefore, NPCs play a functional role in selectively partitioning exportins in the cell nucleus.

暂无摘要。

OBJECTIVE: To explore the expression of cellular apoptosis susceptibility protein （CAS） in acute myeloid leukemia （AML） and its correlation with clinical characteristics.
METHODS: The expression of CAS in bone marrow tissue of 54 patients with AML and 24 patients with non-hematological malignant diseases was detected by Western blot and immune-histochemical method, and compared between AML group and control group. Also the relationship of CAS expression in AML and sex, age, WBC count, Hb, platelet count, bone marrow blast cell ratio, ki-67 index, cytogenetic and molecular biological prognostic risk stratification, extramedullary infiltration and other clinical characteristics was analyzed.
RESULTS: Western blot showed that the expression of CAS protein in bone marrow biopsies of AML patients was significantly higher than that in control group (P<0.05). Immune-histochemical method revealed that CAS was mainly located in the cytoplasm in both AML group and control group. Among 54 AML patients, 14 patients (25.9%) showed high expression of CAS, while all the 24 patients in the control group showed low expression of CAS. The high expression rate of CAS in AML patients was significantly higher than that in the control group (P<0.05). There were statistically significant differences in prognostic risk stratification and the remission rate of the first chemotherapy between CAS high expression group and CAS low expression group in AML (P<0.05). The proportion of high risk patients and unremission patients after the first chemotherapy in CAS high expression group were significantly higher than those in CAS low expression group (57.1% vs 27.5%, 30.8% vs 7.9%), while the proportion of low risk patients and complete remission patients after the first chemotherapy were significantly lower than those in CAS low expression group (14.3% vs 37.5%, 53.8% vs 84.2%). In AML patients, the ki-67 index of bone marrow tissue in CAS high expression group was higher than that in CAS low expression group (60% vs 50%) (P<0.05).
CONCLUSIONS: CAS is localized in cytoplasm in both AML and non-hematological malignant diseases, and its expression increases in AML. CAS is related to the risk stratification of cytogenetics and molecular biology, the remission rate after the first chemotherapy and ki-67 index in AML, which suggests that CAS may be involved in the occurrence and development of AML.
UNASSIGNED: CAS在急性髓系白血病患者中的表达及临床意义.
UNASSIGNED: 探讨急性髓系白血病（AML）中的细胞凋亡易感蛋白（CAS）的表达及其与临床特征的相关性.
UNASSIGNED: 采用蛋白免疫印迹法和免疫组化法检测54例AML患者和24例非血液系统恶性疾病患者骨髓组织中CAS的表达，比较AML组和对照组CAS表达水平，并分析其在AML中的表达与性别、年龄、外周血白细胞数、血红蛋白及血小板计数、骨髓原始细胞比例、ki-67指数、细胞遗传学和分子生物学预后危险度分层、髓外浸润等临床特征的关系.
UNASSIGNED: 蛋白免疫印迹法结果显示，AML患者骨髓活检组织中的CAS蛋白表达显著高于对照组（P<0.05）。免疫组化法检测结果显示，AML组和对照组CAS均主要定位于胞浆。54例AML患者中，CAS高表达者14例（25.9%），对照组24例患者中CAS全部低表达，AML组中CAS高表达率明显高于对照组（P<0.05）。AML患者中CAS高表达组和CAS低表达组之间，预后危险度分层及首次化疗缓解率有差异，且差异有统计学意义（P<0.05）。CAS高表达组的高危患者和首次化疗后未缓解的患者所占比例明显高于CAS低表达组（57.1% vs 27.5% , 30.8% vs 7.9%），低危患者和首次化疗后完全缓解的患者所占比例明显低于CAS低表达组（14.3% vs 37.5% , 53.8% vs 84.2%）。AML患者中，CAS高表达组患者骨髓组织中Ki-67指数高于CAS低表达组（60% vs 50%）（P<0.05）.
UNASSIGNED: CAS在AML和非血液系统恶性疾病中均定位于细胞浆，且在AML中表达量增加，并与患者细胞遗传学和分子生物学预后危险度分层、首次化疗后缓解率及ki-67指数相关，提示CAS可能参与了AML的发生、发展.

The chromosome segregation 1‑like (CSE1L) protein, which regulates cellular mitosis and apoptosis, was previously found to be overexpressed in colorectal cancer (CRC) cells harboring mutations. Therefore, regulating CSE1L expression may confer chemotherapeutic effects against CRC. The gut microflora can regulate gene expression in colonic cells. In particular, metabolites produced by the gut microflora, including the short‑chain fatty acid butyrate, have been shown to reduce CRC risk. Butyrates may exert antioncogenic potential in CRC cells by modulating p53 expression. The present study evaluated the association between CSE1L expression and butyrate treatment from two non‑transformed colon cell lines (CCD‑18Co and FHC) and six CRC cell lines (LS 174T, HCT116 p53+/+, HCT116 p53‑/‑, Caco‑2, SW480 and SW620). Lentiviral knockdown of CSE1L and p53, reverse transcription‑quantitative PCR (CSE1L, c‑Myc and p53), western blotting [CSE1L, p53, cyclin (CCN) A2, CCNB2 and CCND1], wound healing assay (cell migration), flow cytometry (cell cycle analysis) and immunofluorescence staining (CSE1L and tubulin) were adopted to verify the effects of butyrate on CSE1L‑expressing CRC cells. The butyrate‑producing gut bacteria Butyricicoccus pullicaecorum was administered to mice with 1,2‑dimethylhydrazine‑induced colon tumors before the measurement of CSE1L expression. The effects of B. pullicaecorum on CSE1L expression were then assessed by immunohistochemical staining for CSE1L and p53 in tissues from CRC‑bearing mice. Non‑cancerous colon cells with the R273H p53 mutation or CRC cells haboring p53 mutations were found to exhibit significantly higher CSE1L expression levels. CSE1L knockdown in HCT116 p53‑/‑ cells resulted in G1‑and G2/M‑phase cell cycle arrest. Furthermore, in HCT116 p53‑/‑ cells, CSE1L expression was already high at interphase, increased at prophase, peaked during metaphase before declining at cytokinesis but remained relatively high compared with that in HCT116 expressing wild‑type p53. Significantly decreased expression levels of CSE1L were also observed in HCT116 p53‑/‑ cells that were treated with butyrate for 24 h. In addition, the migration of HCT116 p53‑/‑ cells was significantly decreased after CSE1L knockdown or butyrate treatment. Tumors with more intense nuclear p53 staining and weaker CSE1L staining were found in mice bearing DMH/DSS‑induced CRC that were administered with B. pullicaecorum. Taken together, the results indicated that butyrate can impair CSE1L‑induced tumorigenic potential. In conclusion, butyrate‑producing microbes, such as B. pullicaecorum, may reverse the genetic distortion caused by p53 mutations in CRC by regulating CSE1L expression levels.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. However, the treatment regimens for TNBC are limited. Chromosome segregation 1-like (CSE1L), also called cellular apoptosis susceptibility protein (CAS), is highly expressed in breast cancer and plays a crucial role in the progression of various tumours. However, the involvement of CAS in TNBC remains elusive. In this study, we showed that the expression of CAS was higher in TNBC samples than in non-TNBC samples in the Gene Expression Omnibus database. Knockdown of CAS inhibited MDA-MB-231 cell growth, migration and invasion. Further RNA-seq analysis revealed that complement pathway activity was significantly elevated. Of note, complement component 3 (C3), the key molecule in the complement pathway, was significantly upregulated, and the expression of C3 was negatively correlated with that of CAS in breast cancer. Lower C3 expression was related to poor prognosis. Interestingly, the expression level of C3 was positively correlated with the infiltration of multiple immune cells. Taken together, our findings suggest that CAS participates in the development of TNBC through C3-mediated immune cell suppression and might constitute a potential therapeutic target for TNBC.

PHY34 is a synthetic small molecule, inspired by a compound naturally occurring in tropical plants of the Phyllanthus genus. PHY34 was developed to have potent in vitro and in vivo anticancer activity against high grade serous ovarian cancer (HGSOC) cells. Mechanistically, PHY34 induced apoptosis in ovarian cancer cells by late-stage autophagy inhibition. Furthermore, PHY34 significantly reduced tumor burden in a xenograft model of ovarian cancer. In order to identify its molecular target/s, we undertook an unbiased approach utilizing mass spectrometry-based chemoproteomics. Protein targets from the nucleocytoplasmic transport pathway were identified from the pulldown assay with the cellular apoptosis susceptibility (CAS) protein, also known as CSE1L, representing a likely candidate protein. A tumor microarray confirmed data from mRNA expression data in public databases that CAS expression was elevated in HGSOC and correlated with worse clinical outcomes. Overexpression of CAS reduced PHY34 induced apoptosis in ovarian cancer cells based on PARP cleavage and Annexin V staining. Compounds with a diphyllin structure similar to PHY34 have been shown to inhibit the ATP6V0A2 subunit of V(vacuolar)-ATPase. Therefore, ATP6V0A2 wild-type and ATP6V0A2 V823 mutant cell lines were tested with PHY34, and it was able to induce cell death in the wild-type at 246 pM while the mutant cells were resistant up to 55.46 nM. Overall, our data demonstrate that PHY34 is a promising small molecule for cancer therapy that targets the ATP6V0A2 subunit to induce autophagy inhibition while interacting with CAS and altering nuclear localization of proteins.

The transcriptional coactivator with PDZ-binding motif (TAZ) (WWTR1) induces epithelial-mesenchymal transition and enhances drug resistance in multiple cancers. TAZ has been shown to interact with transcription factors in the nucleus, but when phosphorylated, translocates to the cytoplasm and is degraded through proteasomes. Here, we identified a compound TAZ inhibitor 4 (TI-4) that shifted TAZ localization to the cytoplasm independently of its phosphorylation. We used affinity beads to ascertain a putative target of TI-4, chromosomal segregation 1 like (CSE1L), which is known to be involved in the recycling of importin α and as a biomarker of cancer malignancy. We found that TI-4 suppressed TAZ-mediated transcription in a CSE1L-dependent manner. CSE1L overexpression increased nuclear levels of TAZ, whereas CSE1L silencing delayed its nuclear import. We also found via the in vitro coimmunoprecipitation experiments that TI-4 strengthened the interaction between CSE1L and importin α5 and blocked the binding of importin α5 to TAZ. WWTR1 silencing attenuated CSE1L-promoted colony formation, motility, and invasiveness of human lung cancer and glioblastoma cells. Conversely, CSE1L silencing blocked TAZ-promoted colony formation, motility, and invasiveness in human lung cancer and glioblastoma cells. In human cancer tissues, the expression level of CSE1L was found to correlate with nuclear levels of TAZ. These findings support that CSE1L promotes the nuclear accumulation of TAZ and enhances malignancy in cancer cells.

BACKGROUND: Apoptosis-related genes(Args)play an essential role in the occurrence and progression of hepatocellular carcinoma(HCC). However, few studies have focused on the prognostic significance of Args in HCC. In the study, we aim to explore an efficient prognostic model of Asian HCC patients based on the Args.
METHODS: We downloaded mRNA expression profiles and corresponding clinical data of Asian HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. The Args were collected from Deathbase, a database related to cell death, combined with the research results of GeneCards、National Center for Biotechnology Information (NCBI) databases and a lot of literature. We used Wilcoxon-test and univariate Cox analysis to screen the differential expressed genes (DEGs) and the prognostic related genes (PRGs) of HCC. The intersection genes of DEGs and PGGs were seen as crucial Args of HCC. The prognostic model of Asian HCC patients was constructed by least absolute shrinkage and selection operator (lasso)- proportional hazards model (Cox) regression analysis. Kaplan-Meier curve, Principal Component Analysis (PCA) analysis, t-distributed Stochastic Neighbor Embedding (t-SNE) analysis, risk score curve, receiver operating characteristic (ROC) curve, and the HCC data of ICGC database and the data of Asian HCC patients of Kaplan-Meier plotter database were used to verify the model.
RESULTS: A total of 20 of 56 Args were differentially expressed between HCC and adjacent normal tissues (p < 0.05). Univariate Cox regression analysis showed that 10 of 56 Args were associated with survival time and survival status of HCC patients (p < 0.05). There are seven overlapping genes of these 20 and 10 genes, including BAK1, BAX, BNIP3, CRADD, CSE1L, FAS, and SH3GLB1. Through Lasso-Cox analysis, an HCC prognostic model composed of BAK1, BNIP3, CSE1L, and FAS was constructed. Kaplan-Meier curve, PCA, t-SNE analysis, risk score curve, ROC curve, and secondary verification of ICGC database and Kaplan-Meier plotter database all support the reliability of the model.
CONCLUSIONS: Lasso-Cox regression analysis identified a 4-gene prognostic model, which integrates clinical and gene expression and has a good effect. The expression of Args is related to the prognosis of HCC patients, but the specific mechanism remains to be further verified.