The identification and investigation of key molecules involved in the pathogenesis of multiple myeloma (MM) hold paramount clinical significance. This study primarily focuses on elucidating the role of DEPDC1B within the context of MM. Our findings robustly affirm the abundant expression of DEPDC1B in MM tissues and cell lines. Notably, DEPDC1B depletion exerted inhibitory effects on MM cell proliferation and migration while concurrently facilitating apoptosis and G2 cell cycle arrest. These outcomes stand in stark contrast to the consequences of DEPDC1B overexpression. Furthermore, we identified CCNB1 as a putative downstream target, characterized by a co-expression pattern with DEPDC1B, mediating DEPDC1B's regulatory influence on MM. Additionally, our results suggest that DEPDC1B knockdown may activate the p53 pathway, thereby impeding MM progression. To corroborate these in vitro findings, we conducted in vivo experiments that further validate the regulatory role of DEPDC1B in MM and its interaction with CCNB1 and the p53 pathway. Collectively, our research underscores DEPDC1B as a potent promoter in the development of MM, representing a promising therapeutic target for MM treatment. This discovery bears significant implications for future investigations in this field.

Anaplastic thyroid carcinoma (ATC) is the most aggressive subtype of thyroid cancer with few effective therapies. Though immunotherapies such as targeting PD-1/PD-L1 axis have benefited patients with solid tumor, the druggable immune checkpoints are quite limited in ATC. In our study, we focused on the anti-tumor potential of sialic acid-binding Ig-like lectins (Siglecs) in ATC. Through screening by integrating microarray datasets including 216 thyroid-cancer tissues and single-cell RNA-sequencing, SIGLEC family members CD33, SIGLEC1, SIGLEC10 and SIGLEC15 were significantly overexpressed in ATC, among which SIGLEC15 increased highest and mainly expressed on cancer cells. SIGLEC15high ATC cells are characterized by high expression of serine protease PRSS23 and cancer stem cell marker CD44. Compared with SIGLEC15low cancer cells, SIGLEC15high ATC cells exhibited higher interaction frequency with tumor microenvironment cells. Further study showed that SIGLEC15high cancer cells mainly interacted with T cells by immunosuppressive signals such as MIF-TNFRSF14 and CXCL12-CXCR4. Notably, treatment of anti-SIGLEC15 antibody profoundly increased the cytotoxic ability of CD8+ T cells in a co-culture model and zebrafish-derived ATC xenografts. Consistently, administration of anti-SIGLEC15 antibody significantly inhibited tumor growth and prolonged mouse survival in an immunocompetent model of murine ATC, which was associated with increase of M1/M2, natural killer (NK) cells and CD8+ T cells, and decrease of myeloid-derived suppressor cells (MDSCs). SIGLEC15 inhibited T cell activation by reducing NFAT1, NFAT2, and NF-κB signals. Blocking SIGLEC15 increased the secretion of IFN-γ and IL-2 in vitro and in vivo. In conclusion, our finding demonstrates that SIGLEC15 is an emerging and promising target for immunotherapy in ATC.

Anaplastic thyroid cancer (ATC) is one of the deadliest cancers, whose important malignant feature is dedifferentiation. Chromatin remodeling is critical for tumorigenesis and progression, while its roles and regulator in facilitating dedifferentiation of ATC had been poorly understood. In our study, an emerging function of hematological and neurological expressed 1 (HN1) in promoting dedifferentiation of ATC cells was uncovered. HN1 expression was negatively correlated with the thyroid differentiation markers both at mRNA and protein level. Knockdown of HN1 in ATC cells effectively upregulated the thyroid differentiation markers and impeded the sphere formation capacity, accompanying with the loss of cancer stemness. In contrast, overexpression of HN1 drove the gain of stemness and the loss of thyroid differentiation markers. Nude mouse and zebrafish xenograft models showed that inhibition of HN1 in ATC cells effectively hindered tumor growth due to the loss of cancer stemness. Further study showed that HN1 was negatively correlated with CTCF in an independent thyroid-cancer cohort, and inhibition of HN1 enhanced the expression of CTCF in ATC cells. Overexpression of CTCF significantly reversed the dedifferentiation phenotypes of ATC cells, whereas simultaneously inhibiting HN1 and CTCF was unable to recover the level of thyroid differentiation markers. The combination of ATAC-seq and ChIP-seq analysis confirmed that CTCF regulated genes relating with thyroid gland development through influencing their chromatin accessibility. HN1 inhibited the acetylation of H3K27 at the promoter of CTCF by recruiting HDAC2, thereby inhibiting the transcriptional activation of CTCF. These findings demonstrated an essential role of HN1 in regulating the chromatin accessibility of thyroid differentiation genes during ATC dedifferentiation.

The disordered growth, invasion and metastasis of cancer are mainly attributed to bidirectional cell-cell interactions. Extracellular vesicles (EVs) secreted by cancer cells are involved in orchestrating the formation of pre-metastatic niches (PMNs). Tumor-derived EVs mediate bidirectional communication between tumor and stromal cells in local and distant microenvironments. EVs carrying mRNAs, small RNAs, microRNAs, DNA fragments, proteins and metabolites determine metastatic organotropism, enhance angiogenesis, modulate stroma cell phenotypes, restructure the extracellular matrix, induce immunosuppression and modify the metabolic environment of organs. Evidence indicates that EVs educate stromal cells in secondary sites to establish metastasis-supportive microenvironments for seeding tumor cells. In this review, we provide a comprehensive overview of PMN formation and the underlying mechanisms mediated by EVs. Potential approaches to inhibit cancer metastasis by inhibiting the formation of PMNs are also presented.

IntroductionPatients with aggressive lymphomas are at high risk of losing body resources, resulting in malnutrition, immunodeficiency and inferior outcomes. Nutritional status is closely associated with survival, but often neglected in the prognostic assessment. This study aimed to explore the significance of nutritional status in extranodal NK/T-cell lymphoma (ENKTL).MethodsUnivariate and multivariate Cox regression analyses were conducted to examine the significance of nutritional index on overall survival (OS) and progression-free survival (PFS). A nutrition-incorporated score system was constructed based on the multivariate results, and its calibration, discrimination and clinical utility were tested in the training and validation cohort.ResultsMultivariate analysis revealed controlling nutritional status (CONUT) score could independently predict OS (HR 10.247, P=0.001) and PFS (HR 5.587, P=0.001) in addition to prognostic index of natural killer lymphoma plus EBV (PINK-E). Herein, a reformative model, CONUT-PINK-E, was developed and further verified in external validation cohort. CONUT-PINK-E classified patients into three risk grades with significant survival differences (P < 0.001). Compared with the current models, CONUT-PINK-E presented superior discrimination, calibration and clinical benefit.DiscussionIn this study, we firstly verified that CONUT score was efficient to screen prognosis-related malnutrition in ENKTL. Moreover, we developed the first nutritional assessment-covered scoring system, CONUT-PINK-E, which might be a promising tool to provide references for clinical decision-making of ENKTL patients.

Background: Acute lymphoblastic leukemia (ALL) is a malignant lymphoproliferative disease. Although the prognosis of ALL patients has improved significantly in recent years, the 5-year overall survival (OS) rate of adolescent and adult patients is still less than 40%. Recurrence after remission of standard chemotherapy is the most important condition affecting survival, response to initial treatment is the key factor to predict the risk of recurrence, and post-remission therapy (PRT) is an important means to prevent recurrence. In addition, there is growing evidence that minimal residual disease (MRD) plays an important role in the treatment and prognosis assessment of ALL patients, and it is necessary to further stratify the risk of ALL patients to determine who will benefit from chemotherapy or HSCT, and to determine the significance of MRD levels in HSCT decisions in ALL patients. Therefore, we conducted a multicenter study based on MRD levels in adolescent and adult ALL patients to explore the clinical and prognostic significance of post-chemotherapy MRD levels in PRT selection in adolescent and adult ALL patients. Methods: The basic characteristics, cytogenetics, molecular genetics, MRD level, treatment regimen and survival outcome of 404 patients with ALL diagnosed for the first time in Shandong Provincial Hospital, Yantai Yuhuangding Hospital and the Affiliated Hospital of Qingdao University from January 1, 2014 to December 20, 2021 were collected, and the correlation and survival analysis were carried out by SPSS25 software. Results: We studied the effect of MRD levels on the prognosis of patients with B-ALL after chemotherapy, and the guiding significance of different MRD after one course of chemotherapy (MRD1) levels for PRT selection. A total of 182 B-ALL patients with MRD data were included in this part, and the prognosis of patients was analyzed. The results of univariate analysis showed that complete remission was achieved after one induction chemotherapy, MRD1 < 0.01%, MRD after two courses of chemotherapy (MRD2) < 0.01%, MRD after three courses of chemotherapy (MRD3) < 0.01%, patient with standard risk of non-genetic risk stratification and patients in stem cell transplantation (SCT) group had better OS and disease-free survival (DFS), while those older than 35 years old had worse OS (P=0.024). In the multivariate analysis, only MRD3 <0.01% and the way of PRT (CMT or HSCT) were independent prognostic factors for OS and DFS. What's more, MRD2 ≥0.01% (P=0.036) and patients grouped into the chemotherapy (CMT) group (P=0.000) was significantly associated with a high risk of recurrence. Patients were divided into four groups according to the time they reached negative MRD, subgroup A (MRD1−/MRD2±/MRD3±); subgroup B (MRD1+/MRD2−/MRD3±); subgroup C (MRD1+/MRD2+/MRD3−); subgroup D (MRD1+/MRD2+/MRD3+); The results showed that the 5-year OS of subgroup A, B, C and D were 64.75%, 52.15%, 43.85% and 24.32% (P=0.000), and the 5-year DFS were 50.17%, 57.27%, 17.38% and 7.35% (P=0.000), respectively. Achieving negative MRD before transplantation was significantly associated with better OS and DFS. In addition, among the patients with negative MRD1, there was no significant difference in OS between the SCT group and the CMT group. The 5-year OS was 71.9% and 60.9% (P=0.176), respectively. The 5-year DFS was 68.6% and 27.1%, respectively (P=0.004). The recurrence rate in the CMT group was significantly higher than that in the SCT group (45.95% vs 21.43%, P=0.041), but the response rate (64.71%) and survival rate (52.94%) to retreatment after recurrence were high. The prognosis of patients with positive MRD1 was poor. The 5-year OS of patients in CMT group and SCT group were 23.0% and 62.6% (P=0.000), respectively. Conclusion: The earlier the patients were MRD negative after chemotherapy, the better prognosis would achieve. For the patients achieve negative MRD early after chemotherapy, although there was no significant difference in OS between the chemotherapy group and the transplantation group, allo-HSCT could significantly reduce the recurrence rate and obtain better DFS. Of course, this needs to be further verified in prospective randomized controlled trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Background: There has been growing evidence that the aberrantly expressed Homeobox-C 4 (HOXC4) plays crucial roles in the development of some cancer types. However, it remains unclear as far as its expression patterns and prognostic significance are concerned, as is tumor immunity. Methods: To investigate the expression levels and prognostic implications of HOXC4, multiple data sources were used in conjunction with quantitative real-time polymerase chain reaction (qRT-PCR) verification. Afterward, diverse immunological-related analyses, along with anti-cancer drug sensitivity, were performed in a number of cancer types. A further exploration of the underlying mechanisms of HOXC4 in tumorigenesis and immunity was carried out using the Gene Set Enrichment Analysis (GSEA) and the Gene Set Variation Analysis (GSVA). Results: Based on extensive database mining, HOXC4 was ubiquitously expressed across 21 tumor cell lines and significantly higher than that of normal tissues in 21 tumor types. The outcome of survival analysis including overall survival (OS), disease-free interval (DFI), disease-specific survival (DSS) and progression-free interval (PFI) revealed that upregulation of HOXC4 expression in several cancers was associated with worse prognosis. Additionally, HOXC4 was observed to correlate closely with colon adenocarcinoma (COAD), head and neck squamous cell carcinoma (HNSC), lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), rectum adenocarcinoma (READ), and thyroid carcinoma (THCA) in terms of tumor immune cells infiltration. As a result of our comprehensive pan-cancer study, we have identified a significant link between the expression of HOXC4 and the efficacy of immunotherapy-related treatments, together with anti-cancer drug sensitivity. As a final note, HOXC4 was found to modulate multiple signaling pathways involved in tumorigenesis and immunity. Conclusion: HOXC4 has been implicated in our study for the first time as an oncogene in cancers with a poor prognosis, potentially laying the groundwork for promising clinical biomarkers and immunotherapy approaches.

Inflammation involves interactions between various immune cells, inflammatory cells, chemokines and cytokines in pancreatic cancer. Cancer cells as well as surrounding stromal and inflammatory cells establish an inflammatory tumor microenvironment (TME). Inflammation is closely associated with immunity. Meanwhile, immune cells are involved in both inflammation and immune response. Tumor-promoting inflammation and tumor-suppressive immunity are two main characteristics of the tumor microenvironment in pancreatic cancer. Yet, the mechanism of inflammation and immune response in pancreatic cancer development is still unclear due to the dual role of some cytokines and the complicated crosstalk between tumor and stromal components in TME. In this review, we outline the principal cytokines and stromal cells in the pancreatic TME that are involved in the tumor-promoting and immunosuppressive effects of inflammation, and discuss the interaction between inflammation and stromal components in pancreatic cancer progression. Moreover, the clinical approaches based on targeting TME in pancreatic cancer are also summarized. Defining the mechanisms of interplay between inflammation and stromal components will be essential for further development of anti-cancer therapies.

OBJECTIVE:The aim of this study was to determine the biological function of Sprouty 1 (SPRY1) on acute myeloid leukemia (AML), and to investigate the potential mechanism.METHODS:The expression of SPRY1 and the prognostic values of SPRY1 were assessed through the analysis of the Cancer Genome Atlas. Meanwhile, the expression of SPRY1 in AML cells was determined by qRT-PCR and western blot. Then, the biological function of SPRY1 on the proliferation, cell cycle and apoptosis in K-562 and HL-60 cells were tested using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony-formation assay, 5-ethynyl-20-deoxyuridine assay and flow cytometry. Additionally, the protein expressions were measured by western blot.RESULTS:We found that SPRY1 was markedly overexpressed in the cells of the patients with AML, and the patients with AML having a high SPRY1 expression has a bad prognosis. The proliferation and cell cycle progression in K-562 and HL-60 cells were notably promoted by SPRY1 overexpression, but inhibited by SPRY1 knockdown. Meanwhile, the apoptosis of K-562 and HL-60 cells was significantly repressed by SPRY1 overexpression and facilitated by SPRY1 knockdown. In addition, we found that SPRY1 overexpression significantly activated the Hedgehog pathway in AML cells. The function of SPRY1 on the proliferation, cell cycle and apoptosis was reversed by Gli1 in K-562 and HL-60 cells.DISCUSSION:Identifying new biomarkers and exploring the pathogenesis of AML is urgent to improve the disease surveillance for patients with AML.CONCLUSIONS:SPRY1 could facilitate cell proliferation and cell cycle progression, and suppress cell apoptosis via activating the Hedgehog pathway in AML.

Complex interactions occur between tumor cells and the tumor microenvironment. Studies have focused on the mechanism of metabolic symbiosis between tumors and the tumor microenvironment. During tumor development, the metabolic pattern undergoes significant changes, and the optimal metabolic mode of the tumor is selected on the basis of its individual environment. Tumor cells can adapt to a specific microenvironment through metabolic adjustment to achieve compatibility. In this study, the effects of tumor glucose metabolism, lipid metabolism, and amino acid metabolism on the tumor microenvironment and related mechanisms were reviewed. Selective targeting of tumor cell metabolic reprogramming is an attractive direction for tumor therapy. Understanding the mechanism of tumor metabolic adaptation and determining the metabolism symbiosis mechanism between tumor cells and the surrounding microenvironment may provide a new approach for treatment, which is of great significance for accelerating the development of targeted tumor metabolic drugs and administering individualized tumor metabolic therapy.

AIMS:Lung cancer is a key contributor to the cancer-related death throughout the world. FGF21 (fibroblast growth factor 21) has been found to regulate various pulmonary diseases, whereas, the role and mechanism of FGF21 in lung cancer remain unclear. The aim of this research was to explore the expression and function of FGF21 in lung cancer.MAIN METHODS:The mRNA and protein expression of FGF21 were analyzed through qRT-PCR and western blot, respectively. Cell proliferation, apoptosis and migration were analyzed by CCK-8 assay, flow cytometry and wound-healing assay, respectively. ROS, SOD, LDH and CK were examined with respective commercially kit.KEY FINDINGS:FGF21 level was increased in lung cancer tissue samples and cell lines at both mRNA and protein levels. Overexpressing FGF21 promoted cell growth and migration significantly. It also increased SOD and reduced ROS, LDH and CK contents. By contrast, down-regulated FGF21 presented the opposite effect on lung cancer cells. Furthermore, FGF21 may function as a tumor promotor by activating the SIRT1/PI3K/AKT signaling pathway in lung cancer.SIGNIFICANCE:This study demonstrated that FGF21 was a tumor promoter in lung cancer development, serving as a feasible therapeutic target in the treatment of lung cancer.

Nuclear factor, erythroid 2 like 2 (NFE2L2, NRF2) is a transcription factor that regulates various antioxidant enzymes. It plays a vital physiological role in regulating oxidative stress and inflammatory response. However, the roles of NFE2L2 in human cancers are still unclear. Our study is aimed at analyzing the prognostic value of NFE2L2 in pan-cancer and at revealing the relationship between NFE2L2 expression and tumor immunity. The present study revealed that NFE2L2 was abnormally expressed and significantly correlated with mismatch repair (MMR) gene mutation levels and DNA methyltransferase expression in human pan-cancer. In particular, pan-cancer survival analysis indicated that NFE2L2 expression was associated with adverse outcomes—overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI)—in adrenocortical carcinoma (ACC), brain lower grade glioma (LGG), and pancreatic adenocarcinoma (PAAD) patients. A positive relationship was also found between NFE2L2 expression and immune infiltration, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, especially in breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), LGG, liver hepatocellular carcinoma (LIHC), and prostate adenocarcinoma (PRAD). Additionally, NFE2L2 expression was positively correlated with the immune score and the expression of immune checkpoint markers in LGG. In conclusion, these results indicate that transcription factor NFE2L2 is a potential prognostic biomarker and is correlated with immune infiltration in LGG.

Objective: With GPI-anchored protein CD59 as the target, the effect of the abnormal expression of the CD59 gene on the proliferation and apoptosis of cervical cancer HeLa cells was studied to investigate the mechanism of the malignant proliferation of cervical cancer cells. Materials and Methods: Recombinant plasmid pSUPER-siCD59 (CD59 RNA interference) was transfected into HeLa cells via liposome transfection. The plasmid expressed green fluorescent proteins that enabled the observation of the transfection efficiency and was separately transfected. The co-transfection of a pIRES-WTCD59 (wild-type CD59) plasmid, pIRES-MCD59 (with CD59W40 active site mutation) plasmid, and pLeGFP plasmid helped the direct observation of the transfection efficiency, which was examined via an inverted fluorescence microscope at 24, 48, and 72 hours after transfection. Then, the stable transfected cell lines were screened by G418. Western blot, RT-PCR, and immunofluorescence were used to detect the gene and protein expression of CD59 in the stably transfected HeLa cell lines, and the differences were evaluated. The short peptide seal specific to CD59 was exerted on the HeLa cells. Cell proliferation was detected by MTT colorimetric assay, and apoptosis was detected by TUNEL and flow cytometry. Results: The proliferation activity of the HeLa cells with CD59RNAi, CD59W40 active site mutations, and the short peptide seal specific to CD59 significantly decreased. In particular, the proliferation activity of the HeLa cells treated with a high dose of the short peptide seal specific to CD59 was significantly reduced, while the proliferation activity of the HeLa cells with a high expression of CD59 was significantly enhanced. Conclusion: As an inhibitory regulatory protein in the terminal stage of complement regulation, CD59 can promote the proliferation of cervical cancer HeLa cells via inhibiting the dissolution effect of the complement on the cells, promoting transmembrane activation signal transduction, and inhibiting apoptotic signal transduction. Thus, this study provides a new avenue for the clinical treatment of cervical cancer.

OBJECTIVETo intervene the expression of CD59 on cervical cancer HeLa cells by RNA interference and phage display random peptide library, respectively, and detect the effect of down-regulated CD59 expression on proliferation and apoptosis of the cervical cancer cells.METHODSHeLa cells were divided into normal control group, CD59 peptide seal group, pSUPER transfected group and pSUPER-siCD59 transfected group. The CD59 peptide seal group was treated with 10 μg/mL CD59 peptide seal for 8 hours. The pSUPER and pSUPER-siCD59 transfected groups were transfected with empty plasmid pSUPER and recombinant plasmid pSUPER-siCD59, respectively. MTT assay was used for the detection of cell proliferation. TUNEL, annexin V-PE/7-AAD staining combined with flow cytometry were adopted for the detection of cell apoptosis.RESULTSCompared with the control groups, both CD59 peptide seal group and pSUPER-siCD59 transfected group presented a diminished cell proliferation activity and a strengthened apoptosis. What's more, the effect of peptide seal on CD59 expression inhibition was better than that of pSUPER-siCD59 plasmid.CONCLUSIONDown-regulation of CD59 expression could inhibit HeLa cells' proliferation and promote apoptosis, and the inhibitory effect of peptide seal was better than that of CD59 interference plasmid.