Upregulation of long noncoding RNA SNHG20 promotes cell growth and metastasis in esophageal squamous cell carcinoma via modulating ATM-JAK-PD-L1 pathway

Increasing evidence have proved that long noncoding RNAs (lncRNAs) play significant roles in tumorigenesis and development of various cancers. However, the effect of small nucleolar RNA host gene 20 (SNHG20) on the progression of esophageal squamous cell carcinoma (ESCC) remains to be discovered. Herein, we aim to find out the function and the possible mechanism of SNHG20 in ESCC progression. In our study, we demonstrate that SNHG20 is markedly upregulated in ESCC tissues and cell lines. Besides, the level of SNHG20 is closely associated with tumor size, lymph node metastasis, TNM stage, and tumor grade. In addition, SNHG20 level is an independent predictor for clinical outcomes of ESCC patients. Then the gain- and loss-of-function assays reveal that SNHG20 overexpression promotes cell proliferation, migration, invasion, and epithelial-mesenchymal transition as well as represses apoptosis, whereas depletion of SNHG20 exhibits opposite effects. Moreover, we uncover that SNHG20 modulates the expression of ataxia telangiectasia–mutated kinase (p-ATM), p-JAK1/2, and programmed cell death 1 ligand 1 (PD-L1) in ESCC cells and ATM upregulation restores the suppressive effect of SNHG20 inhibition on ESCC progression. Therefore, we conclude that SNHG20 serves as a carcinogen in ESCC by promoting growth and metastasis via ATM-JAK-PD-L1 pathway, supplying a possibly effective therapeutic target for ESCC.     

长链非编码RNA SNHG17通过抑制p57表达促进肺癌进展

目的:分析肺癌中长链非编码RNA(lncRNA)小核仁RNA宿主基因17(SNHG17)与p57的表达相关性及功能联系。方法:通过starBase数据库分析SNHG17和p57在肺癌组织和正常组织中的表达差异;采用人正常肺上皮细胞BEAS-2B和人肺癌细胞系A549、H1975进一步分析SNHG17和p57在肺癌细胞和正常肺细胞中的表达差异;采用qRT-PCR和Western印迹检测si-SNHG17在mRNA和蛋白表达方面对SNHG17和p57的影响;采用CCK-8法检测siSNHG17对A549细胞增殖的影响;采用Transwell法检测si-SNHG17对A549细胞迁移和侵袭能力的影响。结果:通过数据分析发现SNHG17在肺腺癌和肺鳞癌组织中显著高表达,而p57在肺腺癌和肺鳞癌组织中却显著低表达;与正常肺细胞相比,SNHG17和p57在肺癌细胞中的表达趋势与在肺癌组织中一致;SNHG17和p57的表达呈负相关;沉默SNHG17使p57的表达一定程度上调,A549细胞的增殖、迁移和侵袭能力受到抑制。结论:SNHG17在肺癌中高表达,促进肺癌细胞增殖,并通过调节p57的表达来抑制肺癌细胞的增殖和迁移。SNHG17和p57在肺癌中的具体作用机制仍有待进一步研究。     

LncRNA FOXD2‐AS1 as a competitive endogenous RNA against miR‐150‐5p reverses resistance to sorafenib in hepatocellular carcinoma

The current study elucidated the role of a long non‐coding RNA (lncRNA), FOXD2‐AS1, in the pathogenesis of hepatocellular carcinoma (HCC) and the regulatory mechanism underlying FOXD2‐AS1/miR‐150‐5p/transmembrane protein 9 (TMEM9) signalling in HCC. Microarray analysis was used for preliminary screening of candidate lncRNAs in HCC tissues. qRT‐PCR and Western blot analyses were used to detect the expression of FOXD2‐AS1. Cell proliferation assays, luciferase assay and RNA immunoprecipitation were performed to examine the mechanism by which FOXD2‐AS1 mediates sorafenib resistance in HCC cells. FOXD2‐AS1 and TMEM9 were significantly decreased and miR‐150‐5p was increased in SR‐HepG2 and SR‐HUH7 cells compared with control parental cells. Overexpression of FOXD2‐AS1 increased TMEM9 expression and overcame the resistance of SR‐HepG2 and SR‐HUH7 cells. Conversely, knockdown of FOXD2‐AS1 decreased TMEM9 expression and increased the sensitivity of HepG2 and Huh7 cells to sorafenib. Our data also demonstrated that FOXD2‐AS1 functioned as a sponge for miR‐150‐5p to modulate TMEM9 expression. Taken together, our findings revealed that FOXD2‐AS1 is an important regulator of TMEM9 and contributed to sorafenib resistance. Thus, FOXD2‐AS1 may serve as a therapeutic target against sorafenib resistance in HCC.     

长链非编码RNA SNHG7靶向调控miR-9-5p参与舌癌进程

目前发现长链非编码RNA（long non-coding RNA, lncRNA）小核仁RNA宿主基因7 (small nucleolar RNA host gene 7, SNHG7)在多种肿瘤中高表达,发挥原癌基因效应,但是其在舌癌中的功能尚未研究。qRT-PCR结果证实,SNHG7在舌癌组织和细胞中均下调。在舌癌细胞中,过表达SNHG7抑制舌癌细胞增殖,敲低SNHG7促进舌癌细胞增殖。生物信息学分析及双荧光素酶报告基因实验证实,miR-9-5p与SNHG7结合且下调其表达。过表达SNHG7,miR-9-5p表达量降低而自噬/苄氯素1调节因子1（autophagy/Beclin 1 regulator 1, Ambra1）的表达增加。敲低SNHG7,上调miR-9-5p,且降低Ambra1的表达。临床组织标本随访资料统计发现,SNHG7、Ambra1与舌癌患者预后正相关,而miR-9-5p与舌癌患者预后负相关。提示SNHG7/miR-9-5p/Ambra1可作为舌癌预后的潜在标志物。     

LINC01433 promotes hepatocellular carcinoma progression via modulating the miR-1301/STAT3 axis

Long noncoding RNAs (lncRNAs) have been demonstrated to play significant roles in hepatocellular carcinoma (HCC) tumor progression. LINC01433 has been implicated in the progression of lung cancer. However, its biological role in HCC remains poorly understood. In our current study, we focused on the detailed mechanism of LINC01433 in HCC development. First, it was exhibited that LINC01433 was remarkably elevated in HCC cells, which indicated that LINC01433 was involved in HCC. Then, knockdown of LINC01433 was able to restrain HCC cell proliferation and cell colony formation and greatly induced cell apoptosis. On the contrary, overexpression of LINC01433 promoted HCC cell proliferation, increased cell colony formation, and enhanced cell invasion capacity. Subsequently, we found that miR-1301 was remarkably decreased in HCC cells, and it can serve as a target of LINC01433 according to bioinformatics analysis. In addition, the binding correlation between them was validated by performing RNA pull-down experiments and RIP assay. Moreover, STAT3 was predicted and validated as a target of miR-1301, and it was shown that miR-1301 mimics significantly suppressed STAT3 in HCC cells. Finally, in vivo models were established, and the results demonstrated that silencing of LINC01433 could repress HCC development through modulating miR-1301 and STAT3. Taken together, these results indicated in our study that LINC01433 participated in HCC progression through modulating the miR-1301/STAT3 axis and it might act as a novel biomarker in HCC diagnosis and treatment.     

LncRNA SNHG17 promotes gastric cancer progression by epigenetically silencing of p15 and p57

Long noncoding RNAs (lncRNA) are attractive biomarkers and therapeutic targets because of their disease- and stage-restricted expression. Small nucleolar RNA host gene 17 (SNHG17) belongs to a large family of noncoding genes hosting small RNAs, with its expression pattern and biological function not clarified in gastric cancer (GC). Thus, we conducted this study to investigate the functional significance and the underlying mechanisms of SNHG17 in GC progression. Our results showed that SNHG17 expression was upregulated in GC tissues and cells, and its high expression was significantly correlated with increased invasion depth, lymphatic metastasis, and advanced TNM stage. The expression of plasma SNHG17 was also found upregulated in patients with GC compared with healthy controls, with a moderate accuracy for diagnosis of GC (area under the receiver operating characteristic curve = 0.748; 95% CI, 0.666–0.830). Gain- and loss-of-function of SNHG17 revealed that SNHG17 promoted GC cell proliferation, cell cycle progression, invasion, and migration and inhibited apoptosis. Mechanistic investigations showed that SNHG17 was associated with polycomb repressive complex 2 and that this association was required for epigenetic repression of cyclin-dependent protein kinase inhibitors, including p15 and p57, thus contributing to the regulation of GC cell cycle and proliferation. Furthermore, rescue experiments indicated that SNHG17 functioned as an oncogene via activating enhancer of zeste homolog 2 in GC cells. Our study provides a new perspective for SNHG17 acting as a noncoding oncogene in GC tumorigenesis, and it may serve as a novel early diagnostic marker and potential target for the treatment of GC.     

LncRNA DGCR5 represses the development of hepatocellular carcinoma by targeting the miR-346/KLF14 axis

Long non-coding RNAs (lncRNAs) are a class of regulatory noncoding RNAs. Emerging evidence highlights the critical roles of lncRNAs in the progression of hepatocellular carcinoma (HCC). Although many lncRNAs have been identified in the development of HCC, the association between DiGeorge syndrome critical region gene 5 (DGCR5) and HCC remains unclear. In the current study, we focused on the biological role of DGCR5 in HCC. We observed that DGCR5 was decreased in HCC cells, including SMCC7721, Hep3B, HepG2, MHCC-97L, MHCC-97H, and SNU449 hepatocellular carcinoma cells, compared with the normal human liver cell line THLE-3 normal human liver cells. In addition, DGCR5 overexpression could repress HCC cell growth, migration, and invasion considerably. Increasing studies have indicated the interactions between lncRNAs and microRNAs. MicroRNAs are endogenous small noncoding RNAs and they can play important roles in tumorigenesis. MicroRNA 346 (miR-346) has been demonstrated in various human cancer types, including HCC. MiR-346 was found to be increased in HCC cells and DGCR5 can act as a sponge of miR-346 to modulate the progression of HCC. The binding correlation between DGCR5 and miR-346 was validated in our research. Subsequently, Krüppel-like factor 14 (KLF14) was predicted as a downstream target of miR-346 and miR-346 can induce the development of HCC by inhibiting KLF14. Finally, we proved that DGCR5 can rescue the inhibited levels of KLF14 repressed by miR-346 mimics in MHCC-97H and Hep3B cells. Taken together, it was indicated in our study that DGCR5 can restrain the progression of HCC through sponging miR-346 and modulating KLF14 in vitro.     

SNHG12 promotes carcinogenesis of human renal cell cancer via functioning as a competing endogenous RNA and sponging miR-30a-3p

Small nucleolar RNA host gene 12 (SNHG12) has been indicated in the tumorigenesis of various human cancers, including clear cell renal cell carcinoma (ccRCC). However, the underlying mechanisms of SNHG12 driving progression of ccRCC remain incompletely understood. In the present study, we discovered that SNHG12 is up-regulated in ccRCC and that overexpression of SNHG12 predicted poor clinical outcome of ccRCC patients. SNHG12 knockdown notably inhibited proliferation and migration of RCC cells. Furthermore, we discovered that miR-30a-3p, a putative ccRCC inhibitor, was competitively sponged by SNHG12. Via the crosstalk network, SNHG12 was capable of up-regulating multiple target genes of miR-30a-3p, namely, RUNX2, WNT2 and IGF-1R, which have been identified to facilitate tumorigenesis of ccRCC. Taken together, our present study suggested a novel ceRNA network, in which SNHG12 could promote the malignancy of ccRCC although competitively binding with miR-30a-3p and consequently release the expression of its downstream cancer-related genes.     

LINC01133 aggravates the progression of hepatocellular carcinoma by activating the PI3K/AKT pathway

LncRNAs exhibit crucial roles in various pathological diseases, including hepatocellular carcinoma (HCC). Therefore, it is significant to recognize the dysregulated lncRNAs in HCC progression. Recently, LINC01133 has been identified in several tumors. However, the biological role of LINC01133 in HCC remains poorly understood. Currently, we focused on the function of LINC01133 in HCC development. We observed that LINC01133 was significantly increased in HCC cells including HepG2, Hep3B, MHCC-97L, SK-Hep-1, and MHCC-97H cells compared with the normal human liver cell line HL-7702. In addition, PI3K/AKT signaling was highly activated in HCC cells. Knockdown of LINC01133 was able to inhibit HCC cell proliferation, cell colony formation, cell apoptosis, and blocked cell cycle arrest in the G1 phase. For another, downregulation of LINC01133 repressed HCC cell migration and invasion. Subsequently, the PI3K/AKT signaling pathway was strongly suppressed by silence of LINC01133 in Hep3B and HepG2 cells. Then, in vivo tumor xenografts models were established using Hep3B cells to explore the function of LINC01133 in HCC progression. Consistently, our study indicated that knockdown of LINC01133 dramatically repressed HCC tumor progression through targeting the PI3K/AKT pathway in vivo. Taken these together, we revealed that LINC01133 contributed to HCC progression by activating the PI3K/AKT pathway.     

The lncRNA small nucleolar RNA host gene 5 regulates trophoblast cell proliferation,invasion, and migration via modulating miR-26a-5p/N-cadherin axis

Pre-eclampsia (PE) is a pregnancy-specific disease characterized by the occurrence of hypertension and proteinuria after two weeks of gestation. Long noncoding RNAs (lncRNAs) are emerging as key regulators in PE development. This study aims to investigate the role of lncRNA, small nucleolar RNA host gene 5 (SNHG5), in the pathogenesis of PE. The expression of SNHG5 was significantly downregulated in placental tissues from patients with severe PE compared normal controls. Overexpression of SNHG5 promoted trophoblast (HTR-8/SVneo) cell proliferation, invasion, and migration, and flow cytometry results showed that SNHG5 overexpression inhibited apoptosis and caused a decrease of cell population at the G ₀/G ₁ phase and an increase of cell population at the S phase, while knockdown of SNHG5 had the opposite effects. The interaction between SNHG5 and miR-26a-5p was predicted by bioinformatics analysis and confirmed by luciferase reporter assay and RNA immunoprecipitation, and miR-26a-5p was negatively regulated by SNHG5; miR-26a-5p expression was upregulated in PE placental tissues and was inversely correlated with SNHG5 expression. Furthermore, miR-26a-5p was predicted to target the 3′ untranslated region of N-cadherin, which was confirmed by luciferase reporter assay, and miR-26a-5p overexpression suppressed N-cadherin expression in HTR-8/SVneo cells. N-cadherin mRNA expression was downregulated in PE placental tissues and was positively correlated with SNHG5 expression. Both overexpression of miR-26a-5p and knockdown of N-cadherin suppressed HTR-8/SVneo cell invasion and migration, and also attenuated the effects of SNHG5 on the cellular functions of HTR-8/SVneo cells. In conclusion, our study suggested that SNHG5 promotes trophoblast cell proliferation, invasion, and migration at least partly via regulating the miR-26a-5p/N-cadherin axis.     

SNHG16 as the miRNA let-7b-5p sponge facilitates the G2/M and epithelial-mesenchymal transition by regulating CDC25B and HMGA2 expression in hepatocellular carcinoma

Long noncoding RNAs (lncRNAs) play crucial roles in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of small nucleolar RNA host gene 16 (SNHG16) for regulating the cell cycle and epithelial to mesenchymal transition (EMT) remain elusive. In this study, SNHG16 expression profiles of HCC tissues or cell lines were compared with those of normal tissues or hepatocyte cell line. The effect of SNHG16 knockdown in HCC cell lines was investigated by using in vitro loss-of-function experiments and in vivo nude mouse experiments. The potential molecular regulatory mechanism of SNHG16 in HCC progression was investigated by using mechanistic experiments and rescue assays. The results revealed that SNHG16 was highly expressed in HCC tissues and cell lines, which predicted poor prognosis of HCC patients. On one hand, the downregulation of SNHG16 induced G2/M cell cycle arrest, inducing cell apoptosis and suppression of cell proliferation. On the other hand, it inhibited cell metastasis and EMT progression demonstrated by in vitro loss-of-function cell experiments. Besides, knockdown of SNHG16 increased the sensitivity of HCC cells to cisplatin. For the detailed mechanism, SNHG16 was demonstrated to act as a let-7b-5p sponge in HCC. SNHG16 facilitated the G2/M cell cycle transition by directly acting on the let-7b-5p/CDC25B/CDK1 axis, and promoted cell metastasis and EMT progression by regulating the let-7b-5p/HMGA2 axis in HCC. In addition, the mechanism of SNHG16 for regulating HCC cell proliferation and metastasis was further confirmed in vivo by mouse experiments. Furthermore, these results can provide new insights into HCC treatment and its molecular pathogenesis, which may enlighten the further research of the molecular pathogenesis of HCC.     

Long noncoding RNA SNHG15 promotes human breast cancer proliferation,migration and invasion by sponging miR-211-3p

Long non-coding RNAs (lncRNA) have been demonstrated to act as essential regulators in the development and progression of breast cancer. In our study, we found that long noncoding RNA SNHG15 was highly expressed in breast cancer tissues and cell lines. And the expression of SNHG15 was correlated with TNM stage, lymphnode metastasis and survival in breast cancer patients. SNHG15 knockdown significantly inhibited the proliferation and induced apoptosis in breast cancer cells in vitro and in vivo. Besides, SNHG15 downregulation suppressed cell migration and invasion in MCF-7 and BT-20 cells, and inhibited epithelial-mesenchymal transition (EMT). In mechanism, we found that SNHG15 acted as a competing endogenous RNA to sponge miR-211-3p, which was downregulated in breast cancers and inhibited cell proliferation and migration. Our results showed that there was a negative correlation between SNHG15 and miR-211-3p expression in breast cancer patients. Collectively, we, for the first time, revealed the functions of SNHG15 and miR-211-3p in breast cancer.     

miR-125a/b inhibits tumor-associated macrophages mediated in cancer stem cells of hepatocellular carcinoma by targeting CD90

Cancer stem cells promote tumorigenesis and progression of hepatocellular carcinoma (HCC). Recently, emerging evidence indicates tumor-associated macrophages (TAMs) play an important role in tumor progression. However, TAMs often occurs with unknown mechanisms. As an important mediator in intercellular communications, exosomes secreted by host cells mediate the exchange of genetic materials and proteins, which involves tumor aggressiveness. The aim of the study was to investigate whether exosomes derived from TAMs mediate stem cell properties in HCC. TAMs were isolated from the tissues of HCC. microRNA (miRNA) expression profiles of TAMs were analyzed using miRNA microarray. In vitro cell coculture was further conducted to investigate the crosstalk between TAMs and tumor cells mediated by TAMs exosomes. In this study, we showed that TAMs exosomes promote HCC cell proliferation and stem cell properties. Using miRNA profiles assay, we identified significantly lower levels of miR-125a and miR-125b in exosomes and cell lysate isolated from TAMs. Functional studies revealed that the HCC cells were treated with TAM exosomes or transfected with miR-125a/b suppressed cell proliferation and stem cell properties by targeting CD90, a stem cell marker of HCC stem cells. The study indicated that miR-125a/b targeting CD90 played important roles in cancer stem cells of HCC.     

miR-29c targets TNFAIP3, inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma

Recent studies have revealed that microRNA-29c (miR-29c) is involved in a variety of biological processes including carcinogenesis. Here, we report that miR-29c was significantly downregulated in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) cell lines as well as in clinical tissues compared with their corresponding controls. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), a key regulator in inflammation and immunity, was found to be inversely correlated with miR-29c levels and was identified as a target of miR-29c. Overexpression of miR-29c in HepG2.2.15 cells effectively suppressed TNFAIP3 expression and HBV DNA replication as well as inhibited cell proliferation and induced apoptosis. We conclude that miR-29c may play an important role as a tumor suppressive microRNA in the development and progression of HBV-related HCC by targeting TNFAIP3. Thus miR-29c and TNFAIP3 represent key diagnostic markers and potential therapeutic targets for the prevention and treatment of HBV infection.