Cellular Oncology最新文献

Background: TGF-β is related to the function of T cells in the tumor microenvironment. However, the characteristics of TGF-β affecting the function of CD8⁺ T cells in hepatocellular carcinoma (HCC) have not been clearly resolved.

Methods: In this study, flow cytometry, mass cytometry, immunohistochemistry, RNA-seq, single-cell RNA-seq, assay for transposase-accessible chromatin with high throughput sequencing, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were used to study the regulatory effect and molecular mechanism of TGF-β on HCC infiltrating CD8⁺ T cells.

Results: Here, we demonstrated that the overall effect of TGF-β on CD8⁺ T cells in HCC was to activate p-p38 to induce exhaustion, but it also initiated cell-intrinsic resistance mechanisms: 1) TGF-β upregulated the levels of p-STAT1 (S727) and promoted LAIR2 secretion; 2) the TGF-β-p-STAT1-LAIR2 axis relieved CD8⁺ T cells from exhaustion, which we called "self-rescue"; 3) this "self-rescue" behavior showed time and dose limitations on TGF-β stimulation, which was easily masked by stronger inhibitory signals; 4) the function of CD8⁺ T cells was improved by using TAK-981 to amplify "self-rescue" signal.

Conclusion: Our study describes a "self-rescue" mechanism of CD8⁺ T cells in HCC against exhaustion and the good effects from amplifying this signal.

Purpose: Studies have shown that circRNA is involved in the occurrence and development of human cancers. However, it remains unclear that the contribution of circRNA in thyroid carcinoma and its role in the process of tumorigenesis.

Methods: The expression profile of circRNA-miRNA-mRNA in thyroid carcinoma was detected by RNA sequencing and verified by qRT-PCR. The characteristics of circGLIS3 were verified by RNase R and actinomycin assays, subcellular fractionation, and fluorescence in situ hybridization. The functions of circGLIS3 and AIF1L were detected by wound healing, transwell, 3D culture and Western blot. RNA Immunoprecipitation (RIP), RNA pulldown and dual-luciferase reporter assays were used to verify the target genes of circGLIS3 and downstream miRNAs. Functional rescue experiments were performed by transfecting miRNA mimics or siRNA of target genes. Finally, metastatic mouse models were used to investigate circGLIS3 function in vivo.

Results: In this study, we discovered a novel circRNA (has_circ_0007368, named as circGLIS3) by RNA sequencing. CircGLIS3 was down-regulated in thyroid carcinoma tissues and cells line, and was negatively associated with malignant clinical features of thyroid carcinoma. Functional studies found that circGLIS3 could inhibit the migration and invasion of thyroid carcinoma cells, and was related to the EMT process. Mechanistically, circGLIS3 can upregulate the expression of the AIF1L gene by acting as a miR-146b-3p sponge to inhibit the progression of thyroid carcinoma.

Conclusion: Our study identified circGLIS3 as a novel tumor suppressor in thyroid cancer, indicating the potential of circGLIS3 as a promising diagnostic and prognostic marker for thyroid cancer.

Purpose: High-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary, genetic and cellular immunotherapeutic strategies based on the stem and immune cells are emerging as promising treatments against glioblastoma (GBM). We aimed to developed a novel combined immunotherapeutic strategy to improve the treatment efficacy using genetically engineered PBMC-derived induced neural stem cells (iNSCs) expressing HSV-TK and second-generation CAR-NK cells against GBM.

Methods: iNSCs cells expressing HSV-TK (iNSCs^TK) and GD2-specific CAR-NK92 (GD2NK92) were generated from PBMC-derived iNSCs and NK92 cell lines, respectively. The anti-tumor effect of iNSCs^TK and the combinational therapeutics of iNSCs^TK and GD2NK92 were evaluated by GBM cell line using in vitro and in vivo experiments.

Results: PBMC-derived iNSCs^TK possessed tumor-tropism migration ability in vitro and in vivo, which exhibited considerable anti-tumor activity via bystander effect in the presence of ganciclovir (GCV). iNSCs^TK/GCV could slow GBM progression and prolong median survival in tumor-bearing mice. However, the anti-tumor effect was limited to single therapy. Therefore, the combinational therapeutic effect of iNSCs^TK/GCV and GD2NK92 against GBM was investigated. This approach displayed a more significant anti-tumor effect in vitro and in xenograft tumor mice.

Conclusions: PBMC-derived iNSCs^TK showed a significant tumor-tropic migration and an effective anti-tumor activity with GCV in vitro and in vivo. In addition, combined with GD2NK92, iNSCs^TK therapeutic efficacy improved dramatically to prolong the tumor-bearing animal model's median survival.

Purpose: High-risk neuroblastoma (NB) still has an unfavorable prognosis and inducing NB differentiation is a potential strategy in clinical treatment, yet underlying mechanisms are still elusive. Here we identify TRIM24 as an important regulator of NB differentiation.

Methods: Multiple datasets and clinical specimens were analyzed to define the role of TRIM24 in NB. The effects of TRIM24 on differentiation and growth of NB were determined by cell morphology, spheres formation, soft agar assay, and subcutaneous xenograft in nude mice. RNA-Seq and qRT-PCR were used to identify genes and pathways involved. Mass spectrometry and co-immunoprecipitation were used to explore the interaction of proteins.

Results: Trim24 is highly expressed in spontaneous NB in TH-MYCN transgenic mice and clinical NB specimens. It is associated with poor NB differentiation and unfavorable prognostic. Knockout of TRIM24 in neuroblastoma cells promotes cell differentiation, reduces cell stemness, and inhibits colony formation in soft agar and subcutaneous xenograft tumor growth in nude mice. Mechanistically, TRIM24 knockout alters genes and pathways related to neural differentiation and development by suppressing LSD1/CoREST complex formation. Besides, TRIM24 knockout activates the retinoic acid pathway. Targeting TRIM24 in combination with retinoic acid (RA) synergistically promotes NB cell differentiation and inhibits cell viability.

Conclusion: Our findings demonstrate that TRIM24 is critical for NB differentiation and suggest that TRIM24 is a promising therapeutic target in combination with RA in NB differentiation therapy.

Purpose: Chemoresistance is a primary factor for treatment failure and tumor recurrence in non-small cell lung cancer (NSCLC) patients. The oncoprotein survivin is commonly upregulated in human malignancies and is associated with poor prognosis, but its effect on carcinogenesis and chemoresistance in NSCLC is not yet evident, and to explore an effective inhibitor targeting survivin expression is urgently needed.

Methods: The protumor characteristics of survivin and antitumor activities of bergenin in NSCLC cells were examined by MTS, colony formation assays, immunoblot, immunohistochemistry, and in vivo xenograft development.

Results: Survivin was upregulated in non-small cell lung cancer (NSCLC) tissues, while its depletion inhibited NSCLC tumorigenesis. The current study focused on bergenin, identifying its effective antitumor effect on NSCLC cells both in vivo and in vitro. The results showed that bergenin could inhibit cell proliferation and induce the intrinsic pathway of apoptosis via downregulating survivin. Mechanistically, bergenin reduced the phosphorylation of survivin via inhibiting the Akt/Wee1/CDK1 signaling pathway, thus resulting in enhanced interaction between survivin and E3 ligase Fbxl7 to promote survivin ubiquitination and degradation. Furthermore, bergenin promoted chemoresistance in NSCLC cells re-sensitized to pemetrexed treatment.

Conclusions: Survivin overexpression is required for maintaining multiple malignant phenotypes of NSCLC cells. Bergenin exerts a potent antitumor effect on NSCLC via targeting survivin, rendering it a promising agent for the treatment of NSCLC.

Purpose: The transcription factor NF-E2-related factor 2 (NRF2) is a master regulator widely involved in essential cellular functions such as DNA repair. By clarifying the upstream and downstream links of NRF2 to DNA damage repair, we hope that attention will be drawn to the utilization of NRF2 as a target for cancer therapy.

Methods: Query and summarize relevant literature on the role of NRF2 in direct repair, BER, NER, MMR, HR, and NHEJ in pubmed. Make pictures of Roles of NRF2 in DNA Damage Repair and tables of antioxidant response elements (AREs) of DNA repair genes. Analyze the mutation frequency of NFE2L2 in different types of cancer using cBioPortal online tools. By using TCGA, GTEx and GO databases, analyze the correlation between NFE2L2 mutations and DNA repair systems as well as the degree of changes in DNA repair systems as malignant tumors progress.

Results: NRF2 plays roles in maintaining the integrity of the genome by repairing DNA damage, regulating the cell cycle, and acting as an antioxidant. And, it possibly plays roles in double stranded break (DSB) pathway selection following ionizing radiation (IR) damage. Whether pathways such as RNA modification, ncRNA, and protein post-translational modification affect the regulation of NRF2 on DNA repair is still to be determined. The overall mutation frequency of the NFE2L2 gene in esophageal carcinoma, lung cancer, and penile cancer is the highest. Genes (50 of 58) that are negatively correlated with clinical staging are positively correlated with NFE2L2 mutations or NFE2L2 expression levels.

Conclusion: NRF2 participates in a variety of DNA repair pathways and plays important roles in maintaining genome stability. NRF2 is a potential target for cancer treatment.

Purpose: Most patients with acute lymphoblastic leukemia (ALL) are treated with chemotherapy as primary care. Although the treatment response is usually positive, resistance and relapse often occur via unknown mechanisms. The purpose of this study was to identify factors associated with chemotherapy resistance in ALL. Here, we present clinical and experimental evidence that overexpression of nucleolin (NCL), a multifunctional nucleolar protein, is linked to drug resistance in ALL.

Methods: NCL mRNA and protein levels were compared between cell lines and patient samples using qRT-PCR and immunoblotting. NCL mRNA levels were compared between patients of different disease stages from our clinic patients' specimens and publicly available ALL patient datasets. Cells and patient-derived xenograft mouse experiments were performed to assess the effect of NCL inhibition on ALL chemotherapy effectiveness.

Results: Analysis of patient specimens, and publicly available RNA-sequencing datasets revealed a strong correlation between the abundance of NCL and disease relapse or poor survival in B-ALL. Altering NCL expression results in changes in drug sensitivity in ALL cell lines. High levels of NCL upregulated components of the ATP-binding cassette transporters via activation of the ERK pathway, resulting in a decrease in drug accumulation inside the cells. Targeting NCL with AS1411, an NCL-binding oligonucleotide aptamer, significantly increased the sensitivity of ALL cell lines and cells/patient-derived ALL xenograft mice to chemotherapeutic drugs and prolonged mouse survival.

Conclusion: Our results highlight NCL as a prognostic marker in B-ALL and a potential therapeutic target to combat chemotherapy resistance in ALL.

Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent human malignancies, leading to poor prognosis due to its high recurrence and metastasis rates. In recent years it has become increasingly evident that the tumor microenvironment (TME) plays an important role in tumor progression and metastasis. Tumor microenvironment (TME) refers to the complex tissue environment of tumor occurrence and development. Here, we summarize the development of HCC and the role of cellular and non-cellular components of the TME in the metastasis HCC, with particular reference to tumor-infiltrating immune cells. We also discuss some of the possible therapeutic targets for the TME and the future prospectives of this evolving field. SIGNIFICANCE: This review provides a comprehensive analysis of the role of the infiltrating immune cells in TME in the metastasis of HCC and highlights the future outlook for targeted therapy of the TME in the context of recent experiments revealing a number of therapeutic targets targeting the TME.

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second deadliest malignancy worldwide. Current dietary habits are associated with increased levels of iron and heme, both of which increase the risk of developing CRC. The harmful effects of iron overload are related to the induction of iron-mediated pro-tumorigenic pathways, including carcinogenesis and hyperproliferation. On the other hand, iron deficiency may also promote CRC development and progression by contributing to genome instability, therapy resistance, and diminished immune responses. In addition to the relevance of systemic iron levels, iron-regulatory mechanisms in the tumor microenvironment are also believed to play a significant role in CRC and to influence disease outcome. Furthermore, CRC cells are more prone to escape iron-dependent cell death (ferroptosis) than non-malignant cells due to the constitutive activation of antioxidant genes expression. There is wide evidence that inhibition of ferroptosis may contribute to the resistance of CRC to established chemotherapeutic regimens. As such, ferroptosis inducers represent promising therapeutic drugs for CRC.

Conclusions and perspectives: This review addresses the complex role of iron in CRC, particularly in what concerns the consequences of iron excess or deprivation in tumor development and progression. We also dissect the regulation of cellular iron metabolism in the CRC microenvironment and emphasize the role of hypoxia and of oxidative stress (e.g. ferroptosis) in CRC. Finally, we underline some iron-related players as potential therapeutic targets against CRC malignancy.