Enhancer of zeste homolog 2 (EZH2) is enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that can alter downstream target genes expression by trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 could also regulate gene expression in ways besides H3K27me3. Functions of EZH2 in cells proliferation, apoptosis, and senescence have been identified. Its important roles in the pathophysiology of cancer are now widely concerned. Therefore, targeting EZH2 for cancer therapy is a hot research topic now and different types of EZH2 inhibitors have been developed. In this review, we summarize the structure and action modes of EZH2, focusing on up-to-date findings regarding the role of EZH2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. Furtherly, we highlight the advance of targeting EZH2 therapies in experiments and clinical studies.

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EZH2: a novel target for cancer treatment.

Tumor cells can “hijack” chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is gaining increasing attention, since abnormal expression and activity of CCL5 and its receptor CCR5 have been found in hematological malignancies and solid tumors. Numerous preclinical in vitro and in vivo studies have shown a key role of the CCL5/CCR5 axis in cancer, and thus provided the rationale for clinical trials using the repurposed drug maraviroc, a CCR5 antagonist used to treat HIV/AIDS. This review summarizes current knowledge on the role of the CCL5/CCR5 axis in cancer. First, it describes the involvement of the CCL5/CCR5 axis in cancer progression, including autocrine and paracrine tumor growth, ECM (extracellular matrix) remodeling and migration, cancer stem cell expansion, DNA damage repair, metabolic reprogramming, and angiogenesis. Then, it focuses on individual hematological and solid tumors in which CCL5 and CCR5 have been studied preclinically. Finally, it discusses clinical trials of strategies to counteract the CCL5/CCR5 axis in different cancers using maraviroc or therapeutic monoclonal antibodies.

The CCL5/CCR5 Axis in Cancer Progression.

Cervical cancer is a malignant tumour that occurs in the cervix and is classified into two histological types, adenocarcinoma and squamous cell carcinoma (SCC); SCC is more common and accounts for 70% of all cases In 2018 there were ~569,000 new cases of cervical cancer diagnosed worldwide and ~311,000 deaths were attributed to cervical cancer Of these, between 84 and 90% occurred in low- and middle-income countries (LMICs) such as South Africa, India, China and Brazil The most common cause of cervical cancer is persistent infection caused by the sexually transmitted human papilloma virus Other factors that contribute to the incidence of cervical cancer include geography, traditional practices and beliefs, the screening levels, socioeconomic status, healthcare access, public awareness, use of oral contraceptives, smoking and co-infection with HIV An estimated 11 million women from LMICs will be diagnosed with cervical cancer in the next 10-20 years The aim of this review was to explore various types of genetic and epigenetic factors that influence the development, progression or suppression of cervical cancer

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Cervical cancer in low and middle‑income countries (Review)

Long non-coding RNAs (lncRNAs) serve critical roles in the pathogenesis of various cancers, including lung adenocarcinoma (LUAD). Herein, in this study, we aimed to investigate the biological and clinical significance of lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) in LUAD. It was observed that DGCR5 was upregulated in LUAD tissues and LUAD cell lines. Inhibition of DGCR5 can prevent LUAD progression via playing anti-apoptosis roles. Both mRNA expression and protein levels of BCL-2 were increased by DGCR5 downregulation while reversely BAX was increased. Additionally, a novel microRNA target of DGCR5, hsa-mir-22-3p was identified through bioinformatics search and confirmed by dual-luciferase reporter system. Gain and loss-of-function studies were performed to verify whether DGCR5 exerts its biological functions through regulating hsa-mir-22-3p in vitro. Overexpression of DGCR5 was able to reverse the tumor inhibitory effect of hsa-mir-22-3p mimics. Furthermore, in vivo tests tumor xenografts were established to detect the function of DGCR5 in LUAD tumorigenesis. Downregulated DGCR5 expression was greatly associated with smaller tumor size, implying a favorable prognosis of LUAD patients. Taken these together, DGCR5 could be considered as a prognostic biomarker and therapeutic target in LUAD diagnosis and treatment.

LncRNA DGCR5 promotes lung adenocarcinoma (LUAD) progression via inhibiting hsa‐mir‐22‐3p

Lung cancer cells and their sensitivity/resistance to cisplatin chemotherapy: Role of microRNAs and upstream mediators.

EZH2 (enhancer of zeste homolog 2) regulates epigenetic gene silencing and functions as critical regulators in various tumor progression. Macrophages infiltration promotes cancer development via stimulating tumor cell migration and invasion. However, the effect of EZH2 on macrophages infiltration, cell invasion, and migration of lung cancer remains to be investigated. In this study, we found that knockdown of EZH2 inhibited macrophages chemotaxis and decreased chemokine ligand 5 (CCL5). Wound-healing and transwell assays results showed that migration and invasion of lung cancer cells was inhibited by EZH2 deletion. Moreover, EZH2 overexpression increased CCL5 expression. Loss-of functional assay indicated that the promotion ability of EZH2 on macrophages chemotaxis was inhibited by CCL5 knockdown. Mechanistically, the promotion ability of EZH2 on cell migration and invasion of lung cancer was also inhibited by CCL5 knockdown. The in vivo subcutaneous xenotransplanted tumor model also revealed that silence of EZH2 suppressed lung cancer metastasis and macrophages infiltration via regulation of CCL5. In conclusion, our findings indicated that EZH2 promoted lung cancer metastasis and macrophages infiltration via upregulation of CCL5, which might be the underlying mechanism of EZH2-induced lung cancer cell progression.

EZH2 enhances expression of CCL5 to promote recruitment of macrophages and invasion in lung cancer.

Altered microRNA (miR) expression serves an important role in the development and progression of lung cancer. In the present study, the effect of miR-664 on proliferation, migration and invasion of lung cancer cells was assessed. The proliferation of lung cancer cells with an overexpression of miR-664 was examined via MTT assay. The Caspase-Glo3/7 assay was used to examine the effect of miR-664 on cisplatin-induced apoptosis in lung cancer cells. The migration and invasion of lung cancer cells were assessed by Transwell migration and matrigel invasion assays. Western blot analysis was used to examine the protein expression levels. miR-664 improved the proliferation of lung cancer cells and inhibited cisplatin-induced apoptosis of A549 and A427 cells. Furthermore, altered expression of miR-664 affected migration and invasion of lung cancer cells. In addition, a miR-664 mimic decreased E-cadherin expression and increased vementin and Snail expression in lung cancer cells. Notably, the expression level of protein kinase B in A549 cells was changed following altered expression of miR-664. The results of the present study suggest that miR-664 serves an essential role in tumor development and progression in lung cancer.

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microRNA-664 enhances proliferation, migration and invasion of lung cancer cells.

Cell division control (CDC) 42 has been involved in the regulation of diverse cancers. Macrophage recruitment plays an important role in the pathogenesis and development of tumor. However, it remai...

Inhibition of CDC42 reduces macrophage recruitment and suppresses lung tumorigenesis in vivo

Objective To study the expression and clinical significance of P-gp,GST-π and Topo Ⅱα in gastric and colorectal cancers. Methods The expression of P-gp, GST-π and Topo Ⅱα in 83 cases with gastric or colorectal cancer were examined by immunohistochemistry S-P. Results The positive expression rates of P-gp, GST-π, Topo Ⅱα in normal tissue and gastric and colorectal cancers were 69.9% , 65.1% , 50.6% and 83.1% , 85.5%, 45.8% , respectively. The positive rates of P-gp and GST-Ⅱα in gastric and colorectal cancer were significantly higher than those in normal gastric and colorectal tissue （ P 〈 0.05 ）. The expression of Topo Ⅱα in poorly differentiated cancers was significantly higher than that in well- and moderately differentiated cancers. There was no correlation between other items and clinicapathological parameters （ P 〉 0. 05 ）. Conclusion P-gp, GST-π and Topo Ⅱα play important role in muhidrug resistance. Their mechanisms of drug resistance were different. The detection of expression of P-gp, GST-π and Topo Ⅱα has an important guiding significance in chemotherapy for gastric and colorectal cancers.

Key words: 
Stomach neoplasms ;  Colorectal neoplasms ;  P-glycoprotein ;  Glutathione S-transferase-π ;  Topoisomerase Ⅱα

[Expression of P-gp, GST-pi and Topo II alpha in gastric and colorectal cancers and their clinical significance].

Non-small cell lung cancer (NSCLC) has high morbidity and mortality rates worldwide, and tumor metastasis is generally associated with poor prognosis. Chemotherapy resistance aggravates the challenges associated with treating NSCLC. Therefore, identifying effective targets and developing therapies based on these findings could bring novel perspectives for patients with metastatic NSCLC. The expression levels of receptor tyrosine-protein kinase erbB-2 (ERBB2) are associated with NSCLC progression. Differential microRNA (miR) expression profiles have been identified in tumors and can be used to identify multiple malignant phenotypes. miR-133a-3p expression is dysregulated in a variety of tumors. However, to the best of our knowledge, the association between miR-133a-3p and the NSCLC pathogenesis process has not been demonstrated yet. The present study revealed a decrease in miR-133a-3p expression in both tissues and cell lines, which was detected using reverse transcription-quantitative (RT-q)PCR, and western blotting and RT-qPCR demonstrated ERBB2 levels were increased at both protein and mRNA levels. Bioinformatics analysis and dual-luciferase reporter assays demonstrated that ERBB2 was a direct target of miR-133a-3p. Furthermore, MTT, wound healing and Transwell assays revealed that overexpression of miR-133a-3p suppressed proliferation, invasion and migration of NSCLC cells, respectively, effects that were inhibited following ERBB2 overexpression. In addition, immunofluorescence assays demonstrated that overexpression of ERBB2 upregulated N-cadherin expression, while E-cadherin expression was downregulated. In conclusion, the present data demonstrated that miR-133a-3p acted as a tumor suppressor by negatively regulating ERBB2 expression. The miR-133a-3p/ERBB2 axis may be a potential target for the diagnosis and treatment of NSCLC in the future.

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Xinhai Zhu

Papers

EZH2 enhances expression of CCL5 to promote recruitment of macrophages and invasion in lung cancer.

microRNA-664 enhances proliferation, migration and invasion of lung cancer cells.

Inhibition of CDC42 reduces macrophage recruitment and suppresses lung tumorigenesis in vivo

[Expression of P-gp, GST-pi and Topo II alpha in gastric and colorectal cancers and their clinical significance].

MicroRNA-133a-3p suppresses malignant behavior of non-small cell lung cancer cells by negatively regulating ERBB2.