Monday, June 7, 2021

The dual functions of Rab11 and Rab35 GTPases-regulation of cell division and promotion of tumorigenicity

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Am J Cancer Res. 2021 May 15;11(5):1861-1872. eCollection 2021.

ABSTRACT

The broad studies of cancer have led researchers to the creditable understanding of biological and environmental factors that make benign cells to become malignant, as well as the developmental aspects of the tumour cells, known as the "hallmarks of cancer". However, additional research is needed to uncover the features of cancer biology, which would allow to design new and more effective treatment strategies for cancer patients. Since RabGTPases and their effectors are frequently altered in cancer, their role in a regulation of cell division leading to the acquisition of cancer cell-like phenotype has drawn a lot of attention from different research groups in recent years. Both, Rab11 and Rab35 belong to a superfamily of small monomeric GTPases that regulate a diverse array of cellular functions. Lately, Rab11 and Rab35 were declared as oncogenic, and because of their association with abundant cellular functions, a linkage to the induction of cancer, has been proposed. Although the clear connection between the improper regulation of Rab11 or Rab35 and the initiation of tumorigenicity has only beginning to emerge, in this review we will discuss the newest findings regarding the participation of RabGTPases in a control of cell division and promotion of tumorigenesis, trying to link the actual function to the cancer causality.

PMID:34094658 | PMC:PMC8167671

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MiR-22 regulated T cell differentiation and hepatocellular carcinoma growth by directly targeting Jarid2

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Am J Cancer Res. 2021 May 15;11(5):2159-2173. eCollection 2021.

ABSTRACT

MiR-22 has been demonstrated to inhibits tumor growth in several cancers. However, its function in the tumor microenvironment is still unclear, especially for T cell differentiation. Here, miR-22 expression in the circulating T cells from hepatocellular carcinoma (HCC) patients and healthy controls was analyzed with quantitative polymerase chain reaction (qPCR). Diethylnitrosamine (DEN)/phenobarbital (PB)-mediated primary HCC and Hepa1-6 subcutaneous tumor mouse models were established and subjected to lenti-miR-22 injection. Mice immunoreconstituted with miR-22-overexpressing T cells were employed to investigate the antitumor effect of miR-22 in mice. Luciferase assay, immunofluorescent staining, in vitro Th17 cell differentiation assay, and rescue experiments were employed to investigate the mechanism underlying the miR-22-mediated regulation of Th17 cell differ entiation and liver tumor growth. Results confirmed the dramatic downregulation of miR-22 expression in malignant tissues and circulating T cells from patients with HCC. MiR-22 expression correlated with good prognosis of patients. Overexpression of miR-22 impaired the DEN/PB-induced primary HCC formation and the growth of Hepa1-6 subcutaneous tumors by promoting Th17 differentiation. Injection of miR-22-overexpressing T cells in irradiated mice resulted in the inhibition of Hepa1-6 subcutaneous tumor growth via Th17 differentiation promotion. MiR-22 could directly bind to Jarid2, which played an important role during the miR-22-mediated regulation of Th17 differentiation. Taken together, our study expands the understanding of miR-22 function and provides a therapy target for HCC.

PMID:34094675 | PMC:PMC8167680

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The role of iron homeostasis and iron-mediated ROS in cancer

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Am J Cancer Res. 2021 May 15;11(5):1895-1912. eCollection 2021.

ABSTRACT

As an important trace element, iron plays an essential role in many biology processes like cell proliferation, metabolism, and mitochondrial function. However, the disruption of iron homeostasis tends to cells death and human diseases due to it servers as mediator to promote the production of reactive oxygen species (ROS). In this review, first we introduced the mechanism of complex iron-mediated ROS involved in apoptosis, necroptosis, ferroptosis and pyroptosis. Next, we discussed the controversial role of excess iron and iron deficiency in tumor. Finally, we discussed the anti-cancer effects of iron on both sides, and novel iron-related strategies. This review outlined the mechanisms and regulation of iron homeostasis and iron-mediated ROS in tumors, and discussed the iron-related treatments.

PMID:34094660 | PMC:PMC8167679

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HMGA1 induces EZH2 overexpression in human B-cell lymphomas

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Am J Cancer Res. 2021 May 15;11(5):2174-2187. eCollection 2021.

ABSTRACT

EZH2 is an enzymatic subunit of PRC2, an epigenetic regulator that triggers the methylation of the histone H3 lysine 27 silencing the transcription of several genes. EZH2 has a critical role in cancer progression, since its overexpression has been associated with increased cancer cell invasiveness, drug resistance and poor patient survival. However, the mechanisms accounting for EZH2 overexpression in cancer remain still unclear. Intriguingly, also HMGA protein overexpression is a feature of many human malignancies and correlates with the presence of metastases and a poor outcome. The HMGA proteins, including HMGA1 and HMGA2, belong to the architectural transcription factors that play a key role in the organization of chromatin structure. Here, we report a statistically significant correlation between HMGA1 and EZH2 expression in human lymphomas. We demonstrate th at HMGA1 is able to bind EZH2 promoter and induce its activity. Consistently, silencing of HMGA1 expression results in the downregulation of the EZH2 levels leading to a decreased proliferation and migration rate of human lymphoma cell lines. Therefore, these data identify HMGA1 as an EZH2 activator, suggesting a novel molecular mechanism contributing to EZH2 overexpression in human malignancies and a synergism of these proteins in cancer progression.

PMID:34094676 | PMC:PMC8167683

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Background, applications and challenges of radiogenomics in genitourinary tumor

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Am J Cancer Res. 2021 May 15;11(5):1936-1945. eCollection 2021.

ABSTRACT

Genitourinary tumors are groups of tumors with high complexity and heterogeneity. For long-term monitoring, biomarkers that can be used in detection, grading and treatment response assessment are needed. With rapid development in imaging technology and cancer genomics, radiogenomics, the combination of "radiology" and "genomics", has emerged as a powerful tool in oncology practice in recent years because imaging can provide some information that genomic test cannot as gene expression and mutation status are usually evaluated on a small portion of the tumor and are usually not powerful enough to reflect tumor heterogeneity. Radiogenomics investigates the correlations between imaging features and gene expression of a disease, especially in oncologic diseases. It aims to detect the disease's mutation status and supplement genomic analysis based on imaging analysis, p roviding additional findings for diagnosis, treatment decisions, evaluation of treatment response and prognosis prediction of the disease. Recent years have seen an increase in the number of studies investigating the application of radiogenomics in genitourinary tumors. Many studies have shown promising results. However, there still exist limitations and challenges. In this review, we will summarize recent applications of radiogenomics in genitourinary tumors and discuss limitiations, challenges and future directions of radiogenomics.

PMID:34094662 | PMC:PMC8167692

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Role of kruppel-like factor 8 for therapeutic drug-resistant multi-organ metastasis of breast cancer

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Am J Cancer Res. 2021 May 15;11(5):2188-2201. eCollection 2021.

ABSTRACT

Metastasis and drug resistance are intertwined processes that are responsible for the vast majority of patient deaths from breast cancer. The underlying mechanisms remain incompletely understood. We previously demonstrated that KLF8 activates CXCR4 transcription in metastatic breast cancer. Here, we report a novel role of KLF8-CXCR4 signaling for converting single organ metastasis into multiple organ metastasis associated with chemotherapeutic resistance. We show that KLF8 expression in metastatic breast cancer cells can be over-induced by chemotherapeutic drugs. Analysis of data from large-cohorts of patients indicates that post-chemotherapy there is a close correlation between the aberrant high levels of KLF8 and CXCR4 and that this correlation is well associated with drug resistance, metastasis, and poor prognosis. To mimic their aberrant high levels, we overex pressed KLF8 or CXCR4 in a human breast cancer cell line known to metastasize only to the lungs after intravenous injection in nude mice. As expected, these cells become more resistant to chemotherapeutic drugs. Surprisingly, these KLF8 or CXCR4 overexpressing cells, even implanted orthotopically, metastasized extensively to multiple organs particularly the CXCL12-rich organs. Tube formation assay, Ki67 staining and Western blotting revealed that KLF8 or CXCR4 overexpression enhanced angiogenesis involving increased expression and secretion of VEGF protein. We also found that KLF8 or CXCR4 overexpression strongly enhanced formation of filopodium-like protrusions and proliferation via CXCR4 stimulation in a 3D culture model mimicking the colonization step of metastasis. Taken together, these results suggest that the chemo-induction of KLF8 upregulation be critical for drug resistance and systemic metastasis through enhanced tumor angiogenesis and colonization via CXCR4 over-activatio n and that KLF8-CXCR4 signaling axis may be a new therapeutic target for drug-resistant breast cancer metastasis.

PMID:34094677 | PMC:PMC8167685

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Exosomal long noncoding RNA AGAP2-AS1 regulates trastuzumab resistance via inducing autophagy in breast cancer

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Am J Cancer Res. 2021 May 15;11(5):1962-1981. eCollection 2021.

ABSTRACT

Trastuzumab has been widely used for treatment of HER-2-positive breast cancer patients, however, the clinical response has been restricted due to emergence of resistance. Recent studies indicate that long noncoding RNA AGAP2-AS1 (lncRNA AGAP2-AS1) plays an important role in cancer resistance. However, the precise regulatory function and therapeutic potential of AGAP2-AS1 in trastuzumab resistance is still not defined. In this study, we sought to reveal the essential role of AGAP2-AS1 in trastuzumab resistance. Our results suggest that AGAP2-AS1 disseminates trastuzumab resistance via packaging into exosomes. Exosomal AGAP2-AS1 induces trastuzumab resistance via modulating ATG10 expression and autophagy activity. Mechanically, AGAP2-AS1 is associated with ELAVL1 protein, and the AGAP2-AS1-ELAVL1 complex could directly bind to the promoter region of ATG10, inducing H3K27ac and H3K4me3 enrichment, which finally activates ATG10 transcription. AGAP2-AS1-targeting antisense oligonucleotides (ASO) substantially increased trastuzumab-induced cytotoxicity. Clinically, increased expression of serum exosomal AGAP2-AS1 was associate with poor response to trastuzumab treatment. In conclusion, exosomal AGAP2-AS1 increased trastuzumab resistance via promoting ATG10 expression and inducing autophagy. Therefore, AGAP2-AS1 may serve as predictive biomarker and therapeutic target for HER-2+ breast cancer patients.

PMID:34094664 | PMC:PMC8167703

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Minnelide, a prodrug, inhibits cervical cancer growth by blocking HPV-induced changes in p53 and pRb

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Am J Cancer Res. 2021 May 15;11(5):2202-2214. eCollection 2021.

ABSTRACT

HPV-induced cervical cancer is one of the prevalent gynecological cancers world-wide. In the present study, we determined the efficacy of Minnelide, a prodrug which is converted to its active form (Triptolide) in vivo against cervical cancer cells. Our studies show that Triptolide inhibited HPV-16 and HPV-18 positive cells at nanomolar concentrations. Tumor cells treated with Triptolide failed to grow in 3-D cultures in a concentration-dependent manner. Triptolide markedly reduced E6 and E7 transcript levels. Further studies revealed that exposure to Triptolide increased the levels of p53 and pRb. As a consequence, Caspase-3/7 activation and apoptosis was induced in cervical cancer cells by Triptolide. Subsequently, we evaluated the efficacy of Minnelide in xenotransplantation models of cervical cancer. Minnelide at very low doses effectively inhibited the growth of established cervical cancers in all the three animal models tested. Furthermore, Minnelide treatment was more effective when combined with platinum-based chemotherapy. These studies show that Minnelide can be used to inhibit the growth of cervical cancer.

PMID:34094678 | PMC:PMC8167699

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Boosting immune surveillance by low-dose PI3K inhibitor facilitates early intervention of breast cancer

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Am J Cancer Res. 2021 May 15;11(5):2005-2024. eCollection 2021.

ABSTRACT

Prevention of estrogen receptor-negative (ER-) breast cancer is an unmet challenge, although tamoxifen and aromatase inhibitors can successfully decrease the incidence of ER-positive (ER+) breast cancer. PI3K pathway activation has been detected in tamoxifen-resistant ER- breast lesions of patients. Here, we further ratified that the PI3K pathway is significantly activated in premalignant ER- breast lesions compared with paired normal tissues of patients, which prompted our assessment of targeting PI3K on inhibition of ER- mammary tumor initiation and progression. Both genetic knockdown of PIK3CA or intervention with low-doses of a PI3K inhibitor (GDC-0941) prevented the dysplasia phenotype of semi-transformed human ER- mammary epithelial cells in 3-dimensional culture in vitro. Importantly, low-dose GDC-0941 treatment significantly delayed mammary tumor in itiation in the MMTV-neu mouse model without exhibiting discernable adverse effects. Interestingly, increased CD8+/GZMB+ T-cells were detected in mammary tissue after GDC-0941 treatment, suggesting enhanced immune surveillance. Mechanistically, elevated expression of potent T-cell chemo-attractants, including CCL5 and CXCL10, were detected both in vitro and in vivo after GDC-0941 treatment. Furthermore, inhibition of PI3K significantly increased T-cell recruitment in a CCL5/CXCL10-dependent manner. In human ER- breast cancer, PI3K activation is correlated with significantly reduced CCL5, CXCL10 and CD8A expression, suggesting that the decreased CD8+ T-cell recruitment and escape of immune surveillance may contribute to ER- breast cancer development. In summary, our study indicates that low-dose PI3K inhibitor treatment may intervene early stage ER- breast cancer development by enhancing immune surveillance via CCL5/ CXCL10.

PMID:34094666 | PMC:PMC8167687

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HMGB1 promotes tumor progression and invasion through HMGB1/TNFR1/NF-kappaB axis in castration-resistant prostate cancer

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Am J Cancer Res. 2021 May 15;11(5):2215-2227. eCollection 2021.

ABSTRACT

Prostate cancer (PCa) is the most common male cancer. Most patients treated with androgen deprivation therapy progress to castration-resistant PCa. To overcome the limitations of this treatment, there is an urgent need to identify more effective treatment targets. High mobility group box 1 protein (HMGB1) is known to be associated with progression, metastasis, and poor prognosis of several solid tumors; however, its role in PCa remains unclear. Thus, we aimed to evaluate the clinical significance and biological roles and mechanism of HMGB1 in PCa. We showed that increased expression of HMGB1 correlated with increased risk of aggressive PCa, and high expression of HMGB1 was associated with poor biochemical recurrence-free survival in a Korean cohort. Additionally, the inhibition of HMGB1 expression significantly reduced cell proliferation, invasive capacity, and NF -κB signaling in vitro. Our results indicated that HMGB1 is a critical factor in the development and progression of PCa. Moreover, we found that HMGB1 directly interacts with TNFR1, and TNFR1 overexpression in HMGB1 knockdown cells reversed the effects of HMGB1 knockdown. Importantly, our results suggest that HMGB1 binding to TNFR1 promotes tumor progression by activating the NF-κB signaling pathway in PCa; therefore, the HMGB1/TNFR1/NF-κB signaling pathway could serve as a novel therapeutic target for improving PCa therapy.

PMID:34094679 | PMC:PMC8167672

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BRCA1-associated protein 1 serves as a tumor suppressor in hepatocellular carcinoma by deubiquitinating and stabilizing PTEN

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Am J Cancer Res. 2021 May 15;11(5):2044-2061. eCollection 2021.

ABSTRACT

BRCA1-associated protein 1 (BAP1) or its mutants have been known to play critical regulatory roles in tumor biology, yet their role in hepatocellular carcinoma (HCC) remains largely unclear. In this study, we detected the mutations of all the exons of BAP1 in 105 HCC patients using Sanger sequencing, and found eight somatic mutations in 6 (5.71%) patients. We also found that the mRNA and protein levels of BAP1 were markedly downregulated in HCC versus the adjacent non-tumor tissues. Wild-type BAP1 but not mutant BAP1 significantly inhibited HCC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) in vitro, and tumor progression and metastasis in vivo. Mechanistically, BAP1 complexed with PTEN and stabilized PTEN via deubiquitination and, furthermore, negatively regulated HCC cell EMT by deactivating the AKT/GSK-3β/Snail pathway. How ever, those tumor-inhibitory effects of BAP1 were abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated to aggressive tumor phenotypes, which also independently associated with poorer recurrence-free survival and overall survival after curative hepatectomy. Conclusively, our results indicate that BAP1, significantly downregulated, somatically mutated and negatively regulating EMT in HCC, serves as a tumor suppressor of HCC by deubiquitinating and stabilizing PTEN.

PMID:34094668 | PMC:PMC8167693

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