RESUMO
Cervical cancer (CC) remains one of the most common female malignancies, with higher incidence and mortality rates. more than 99% of CCs are associated with persistent infection with high-risk human papillomavirus. In view of the growing evidence that HPV 16 E6 and E7, two key oncoproteins encoded by HPV 16, regulate the expression of many other multifunctional genes and downstream effectors that contribute to the development of CC. Herein, we undertook a comprehensive effort into how HPV16 E6, E7 oncogenes affect the progression of CC cells. Previous studies have shown that ICAT expression was significantly increased in CC and had a pro-cancer effect. We observed that knockdown of HPV16 E6, E7 expression in SiHa and CasKi cells resulted in significant inhibition of ICAT expression and upregulation of miR-23b-3p expression. Besides, dual luciferase assays confirmed that ICAT was a target gene of miR-23b-3p, and negatively modulated by miR-23b-3p. Functional experiments showed that the overexpression of miR-23b-3p suppressed malignant behaviors of CC cells, such as migration, invasion and EMT. The overexpression of ICAT counteracted the suppressive effect of miR-23b-3p on HPV16-positive CC cells. Furthermore, after the knockdown of HPV16 E6 and E7, the inhibition of miR-23b-3p could increase the ICAT expression and rescue the siRNA HPV16 E6, E7-mediated suppressive impact on the aggressiveness of SiHa and CaSki cells. Collectively, our findings uncover that HPV16 E6, E7/miR-23b-3p/ ICAT axis plays an important role in HPV16-positive CC pathogenesis, which may serve as a promising therapeutic target for HPV16-associated CC.
Assuntos
MicroRNAs , Proteínas Oncogênicas Virais , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Papillomavirus Humano 16/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proliferação de Células/genética , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismoRESUMO
BACKGROUND: Research on the role of lncRNAs in the process of bone metastasis in breast cancer (BM-BCa) has just begun at an early stage, and an increasing number of lncRNAs have been proved to play a regulatory role in the process of BM-BCa. Our study focused on the balance of osteogenic-osteoclast regulated by lncRNA-SNHG3 in bone metastasis microenvironment. METHODS: SNHG3 level of clinical tissues and breast cancer cell lines was determined by RT-qPCR. ALP staining, ALP activity identification and western blotting of OPG, OSX, RUNX2, BMP2 together with BMP3 was performed to verify the osteogenesis of bone marrow mesenchymal stem cells (BMSCs) both in vitro and in vivo. Exosomes derived from MDA-MB-231 were characterized and sequenced, followed by RT-qPCR. Dual luciferase reporter gene assay was utilized to analyze the binding sites of miR-1273g-3p on SNHG3 and BMP3. RESULTS: Expression of BMP3 was positively regulated by SNHG3 via exosomal miR-1273g-3p. CONCLUSION: The overexpression of SNHG3 in breast cancer cells may be responsible for osteolytic metastasis Thus, knockdown of SNHG3 might be a potential target for improvement of BM-BCa Treatment.
Assuntos
Proteína Morfogenética Óssea 3/genética , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/metabolismo , Regiões 3' não Traduzidas , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Diferenciação Celular , Exossomos , Feminino , Humanos , Células MCF-7 , Metástase Neoplásica , Osteogênese , Microambiente TumoralRESUMO
We previously reported that BMP9 inhibited breast cancer progression. However, the precise molecular mechanism is still unknown. Based on our RNA-sequencing (RNA-seq) results, BMP9 significantly down-regulated the expression of long non-coding RNA SNHG3. Exogenous BMP9 promoted autophagy and inhibited migration and invasion in MDA-MB-231 cells, which was effectively blunted by SNHG3 overexpression. Interestingly, SNHG3 was negatively connected with autophagy. Knockdown of SNHG3 induced autophagy by increasing the formation of autophagic vacuoles and thus inhibited the migration and invasion of MDA-MB-231 cells. Mechanically, BMP9-SNHG3 activated AMPK, AKT and mTOR signaling pathways to induce autophagy and inhibit migration and invasion. Meanwhile, BMP9 regulated SNHG3 transcription by suppressing c-Myc entry into the nucleus. In conclusion, BMP9 promotes autophagy and inhibits migration and invasion in breast cancer cells through the c-Myc/SNHG3/mTOR signaling axis, which might offer a fresh perspective on BMP9's breast cancer-inhibiting properties.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Autofagia/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Regulator of chromatin condensation 1 (RCC1) is the major guanine nucleotide exchange factor of RAN GTPase, which plays a key role in various biological processes such as cell cycle and DNA damage repair. Small nucleolar RNA host gene 3 (SNHG3) and small nucleolar RNA host gene12 are long-stranded non-coding RNAs (lncRNAs) and are located on chromatin very close to the sequence of Regulator of chromatin condensation 1. Many studies have shown that they are aberrantly expressed in tumor tissues and can affect the proliferation and viability of cancer cells. Although the effects of Regulator of chromatin condensation 1/small nucleolar RNA host gene 3/small nucleolar RNA host gene12 on cellular activity have been reported, respectively, their overall analysis on the pan-cancer level has not been performed. Here, we performed a comprehensive analysis of Regulator of chromatin condensation 1/small nucleolar RNA host gene 3/small nucleolar RNA host gene12 in 33 cancers through the Cancer Genome Atlas and Gene Expression Database. The results showed that Regulator of chromatin condensation 1/small nucleolar RNA host gene 3/small nucleolar RNA host gene12 were highly expressed in a variety of tumor tissues compared to normal tissues. The expression of Regulator of chromatin condensation 1/small nucleolar RNA host gene 3/small nucleolar RNA host gene12 in BRCA, LGG and LIHC was associated with TP53 mutations. In addition, Regulator of chromatin condensation 1/small nucleolar RNA host gene 3/small nucleolar RNA host gene12 expression was closely associated with the prognosis of patients with multiple tumors. Immunocorrelation analysis indicated that Regulator of chromatin condensation 1/small nucleolar RNA host gene 3/small nucleolar RNA host gene12 showed a correlation with multiple immune cell infiltration. The results of enrichment analysis suggested that Regulator of chromatin condensation 1/small nucleolar RNA host gene 3/small nucleolar RNA host gene12 was involved in the regulation of cell cycle, apoptosis and other pathways. We found that these effects were mainly mediated by Regulator of chromatin condensation 1, while the trend of small nucleolar RNA host gene 3/small nucleolar RNA host gene12 regulation was also consistent with regulator of chromatin condensation 1. The important role played by Regulator of chromatin condensation 1 in tumor diseases was further corroborated by the study of adjacent lncRNAs.These findings provide new and comprehensive insights into the role of Regulator of chromatin condensation 1/small nucleolar RNA host gene 3/small nucleolar RNA host gene12 in tumor development and show their potential as clinical monitoring and therapy.