p53 hydroxylation by JMJD6 represents a novel post-translational modification for p53. JMJD6-mediated hydroxylation regulates p53's transcriptional activity and the p53-dependent control of colon cancer.
Radioresistance is an important challenge for clinical treatments. The main causes of radioresistance include hypoxia in the tumor microenvironment, the antioxidant system within cancer cells, and the upregulation of DNA repair proteins. Here, a multiple radiosensitization strategy of high‐Z‐element‐based radiation enhancement is designed, attenuating hypoxia and microRNA therapy. The novel 2D graphdiyne (GDY) can firmly anchor and disperse CeO2 nanoparticles to form GDY–CeO2 nanocomposites, which exhibit superior catalase‐mimic activity in decomposing H2O2 to O2 to significantly alleviate tumor hypoxia, promote radiation‐induced DNA damage, and ultimately inhibit tumor growth in vivo. The miR181a‐2‐3p (miR181a) serum levels in patients are predictive of the response to preoperative radiotherapy in locally advanced esophageal squamous cell carcinoma (ESCC) and facilitate personalized treatment. Moreover, miR181a can act as a radiosensitizer by directly targeting RAD17 and regulating the Chk2 pathway. Subsequently, the GDY–CeO2 nanocomposites with miR181a are conjugated with the iRGD‐grafted polyoxyethylene glycol (short for nano‐miR181a), which can increase the stability, efficiently deliver miR181a to tumor, and exhibit low toxicity. Notably, nano‐miR181a can overcome radioresistance and enhance therapeutic efficacy both in a subcutaneous tumor model and human‐patient‐derived xenograft models. Overall, this GDY–CeO2 nanozyme and miR181a‐based multisensitized radiotherapy strategy provides a promising therapeutic approach for ESCC.
Accumulating evidence indicates that microRNAs (miRNAs) are involved in regulating cancer invasion and metastasis, and an increasing number of research demonstrates that miRNAs can promote or inhibit cell motility depending on genetic background of different cancers and the microenvironment. In the present study, we established an in vivo bone metastasis model of breast cancer by injecting MDA-MB-231 cells into the left ventricle of nude mice, and then screened the differentially expressed miRNAs between parental and bone-metastatic MDA-MB-231 cells using miRNA array. The results revealed that decreased expression of miR-429 was probably involved in negatively regulating bone metastasis of breast cancer cells. On the other hand, overexpression of miR-429 in MDA-MB-231 cells remarkably suppressed invasion in vitro. We identified ZEB1 and CRKL as potential targets of miR-429 by analyzing combined results from in silico search and global expression array of the same RNA samples. Immunoblot assay confirmed that miR-429 reduced their expression at protein level. Taken together, our results offer an opportunity for further understanding of the recondite mechanisms underlying the bone metastasis of breast cancer.
PI3K and STAT3 are frequently activated in cancer progression. However, little is known about the underlying mechanisms by which PI3K and STAT3 regulate head and neck squamous cell cancer (HNSCC) growth. The lncRNA HOX transcript antisense RNA () was found to modulate the progression of HNSCC. In this study, we attempted to establish the correlation of PI3K/STAT3/HOTAIR signaling with the progression of HNSCC and its sensitivity toward platinum-based and targeted anti-EGFR combination therapy. We first analyzed the STAT3/HOTAIR and PI3K/AKT level in human HNSCC samples. We then activated or suppressed STAT3/HOTAIR and determined the effects on HNSCC cell proliferation and the growth of UM1 xenograft tumor, an orthotopic model of HNSCC. The sensitivity of HNSCC cells toward cisplatin and cetuximab was determined by assays. HNSCC samples showed significantly robust expression/activation of STAT3, HOTAIR, PI3K, and AKT, compared with normal squamous epithelium. STAT3 inhibition with WP1066 decreased HOTAIR level and sensitized HNSCC to cisplatin or cetuximab. STAT3 promoted HOTAIR transcription and its interaction with pEZH2-S21, resulting in enhanced growth of HNSCC cells. In addition, overexpression of HOTAIR promoted the growth of UM1 xenograft tumors Our results suggest that STAT3 signaling promotes HNSCC progression via regulating HOTAIR and pEZH2-S21 in HNSCC with PI3K overexpression/activation. These findings provide a rationale to target the STAT3/HOTAIR/pEZH2-S21 regulatory axis for treating patients with HNSCC..
Invasion and metastasis are major contributors to cancer-caused death in patients suffered from esophageal squamous cell carcinoma (ESCC). To explore the microRNAs involved in regulating invasion-metastasis cascade of ESCC, we established two pairs of sublines (30-U/D and 180-U/D) with distinct motility capacity from two ESCC cell lines (KYSE30 and KYSE180). Screening of the differentially expressed microRNAs identified that microRNA-92b-3p (miR-92b) could dramatically inhibit invasion and metastasis of ESCC cells in vitro and in vivo. Subsequent studies showed that miR-92b exerted its inhibitory function through suppressing the expression of integrin αV (ITGAV), which further reduced phosphrylated FAK and impaired Rac1 activation. Moreover, higher expression of miR-92b in ESCC tissues correlated inversely with lymph node metastasis and indicated better prognosis. Together, these results for the first time describe how miR-92b suppresses the motility of ESCC cells and provide a promise for diagnosis or therapy of ESCC invasion and metastasis.
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