LncRNA LINC01006 facilitates cell proliferation, migration and EMT in lung adenocarcinoma via targeting miR-129-2-3p/CTNNB1 axis and activating Wnt/β-catenin signaling pathway

Animal Experiments ◽

Luciferase Reporter ◽

Lung adenocarcinoma (LUAD) is a common type of malignancy of lung cancers. Long intergenic non-coding RNAs (lincRNAs) have emerged as crucial regulators of various cancers, including LUAD. LINC01006 is a newly discovered lncRNA whose function in LUAD remains to be explored. This study is to explore the role of LINC01006 in LUAD. Quantitative real-time PCR (RT-qPCR) analysis and western blot were used to determine the expressions and protein levels respectively. Functional assays and animal experiments investigated the role of LINC01006 both in vivo and in vitro. Moreover, TOP/FOP assay was performed to detect the activation of Wnt/β-catenin signaling pathway. The interaction between LINC01006 and miR-129-2-3p/catenin beta 1 (CTNNB1) was explored by RNA binding protein immunoprecipitation (RIP), RNA pull down, luciferase reporter assays and rescue experiments. According to the results, LINC01006 was highly expressed in LUAD tissues and cell lines. LINC01006 knockdown significantly suppressed cell proliferative, migratory, epithelial-mesenchymal transition (EMT) capacities and the tumor development. Moreover, LINC01006 enhanced CTNNB1 via sequestering miR-129-2-3p and activated Wnt/β-catenin pathway in LUAD. Overall, LINC01006 promotes LUAD development via activating Wnt/β-catenin pathway, implying that LINC01006 might be a promising biomarker for LUAD treatment.

Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

Cell Death and Disease ◽

10.1038/s41419-020-03259-2 ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Hongli Li ◽

Qingjie Mu ◽

Guoxin Zhang ◽

Zhixin Shen ◽

Yuanyuan Zhang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Molecular Mechanisms ◽

Ectopic Expression ◽

Tumor Development ◽

Biological Significance ◽

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

microRNA-382 suppresses the progression of pancreatic cancer through the PI3K/Akt signaling pathway by inhibition of Anxa3

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00322.2019 ◽

2020 ◽

Vol 319 (3) ◽

pp. G309-G322

Author(s):

Xiaohui Wan ◽

Dongrui Guo ◽

Qi Zhu ◽

Rongfeng Qu

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Mesenchymal Transition ◽

Node Metastasis

This study focused on the mechanism of miR-382 in epithelial mesenchymal transition and lymph node metastasis in PC in relation to Anxa3 and the PI3K/Akt signaling pathway. We found the inhibitory role of miR-382 in PC in vitro and in vivo.

METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer

Molecular Cancer ◽

10.1186/s12943-019-1065-4 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 49

Author(s):

Ben Yue ◽

Chenlong Song ◽

Linxi Yang ◽

Ran Cui ◽

Xingwang Cheng ◽

...

Keyword(s):

Gastric Cancer ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Qrt Pcr ◽

Rna Immunoprecipitation ◽

E Cadherin

Abstract Background As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its functions in tumor epithelial-mesenchymal transition (EMT) and metastasis remain obscure. Methods qRT-PCR and immunohistochemistry were used to evaluate the expression of methyltransferase-like 3 (METTL3) in gastric cancer (GC). The effects of METTL3 on GC metastasis were investigated through in vitro and in vivo assays. The mechanism of METTL3 action was explored through transcriptome-sequencing, m6A-sequencing, m6A methylated RNA immunoprecipitation quantitative reverse transcription polymerase chain reaction (MeRIP qRT-PCR), confocal immunofluorescent assay, luciferase reporter assay, co-immunoprecipitation, RNA immunoprecipitation and chromatin immunoprecipitation assay. Results Here, we show that METTL3, a major RNA N6-adenosine methyltransferase, was upregulated in GC. Clinically, elevated METTL3 level was predictive of poor prognosis. Functionally, we found that METTL3 was required for the EMT process in vitro and for metastasis in vivo. Mechanistically, we unveiled the METTL3-mediated m6A modification profile in GC cells for the first time and identified zinc finger MYM-type containing 1 (ZMYM1) as a bona fide m6A target of METTL3. The m6A modification of ZMYM1 mRNA by METTL3 enhanced its stability relying on the “reader” protein HuR (also known as ELAVL1) dependent pathway. In addition, ZMYM1 bound to and mediated the repression of E-cadherin promoter by recruiting the CtBP/LSD1/CoREST complex, thus facilitating the EMT program and metastasis. Conclusions Collectively, our findings indicate the critical role of m6A modification in GC and uncover METTL3/ZMYM1/E-cadherin signaling as a potential therapeutic target in anti-metastatic strategy against GC.

TFAP2A potentiates lung adenocarcinoma metastasis by a novel miR-16 family/TFAP2A/PSG9/TGF-β signaling pathway

Cell Death and Disease ◽

10.1038/s41419-021-03606-x ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Yanlu Xiong ◽

Yangbo Feng ◽

Jinbo Zhao ◽

Jie Lei ◽

Tianyun Qiao ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Biological Function ◽

Transforming Growth Factor Β ◽

Mesenchymal Transition ◽

Node Metastasis

AbstractTranscription factor AP-2α (TFAP2A) was previously regarded as a critical regulator during embryonic development, and its mediation in carcinogenesis has received intensive attention recently. However, its role in lung adenocarcinoma (LUAD) has not been fully elucidated. Here, we tried to investigate TFAP2A expression profiling, clinical significance, biological function and molecular underpinnings in LUAD. We proved LUAD possessed universal TFAP2A high expression, indicating a pervasively poorer prognosis in multiple independent datasets. Then we found TFAP2A was not indispensable for LUAD proliferation, and exogenous overexpression even caused repression. However, we found TFAP2A could potently promote LUAD metastasis possibly by triggering epithelial–mesenchymal transition (EMT) in vitro and in vivo. Furthermore, we demonstrated TFAP2A could transactivate Pregnancy-specific glycoprotein 9 (PSG9) to enhance transforming growth factor β (TGF-β)-triggering EMT in LUAD. Meanwhile, we discovered suppressed post-transcriptional silencing of miR-16 family upon TFAP2A partly contributed to TFAP2A upregulation in LUAD. In clinical specimens, we also validated cancer-regulating effect of miR-16 family/TFAP2A/PSG9 axis, especially for lymph node metastasis of LUAD. In conclusion, we demonstrated that TFAP2A could pivotally facilitate LUAD progression, possibly through a novel pro-metastasis signaling pathway (miR-16 family/TFAP2A/PSG9/ TGF-β).

LDH-A promotes malignant behavior via activation of epithelial-to-mesenchymal transition in lung adenocarcinoma

Bioscience Reports ◽

10.1042/bsr20181476 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 11

Author(s):

Xiao-ming Hou ◽

Shu-qiao Yuan ◽

Da Zhao ◽

Xiao-jun Liu ◽

Xin-an Wu

Keyword(s):

Tumor Growth ◽

Lung Adenocarcinoma ◽

Cancer Cells ◽

Colony Formation ◽

Xenograft Model ◽

Abstract Lactate dehydrogenase A (LDH-A) is a key enzyme during glycolysis, which increases the synthesis of related proteins and has elevated activity in cancer cells. The role of LDH-A in lung adenocarcinoma (LUAD) progression was investigated in the present study. Expression levels of LDH-A were assessed in LUAD samples, and the relationship between LDH-A expression status and the prognosis of LUAD patients was confirmed. The effect of LDH-A on proliferation, invasion, migration, and colony formation of cancer cells was assessed. We further determined the role of LDH-A in tumor growth in vivo by using xenograft LUAD tumor models. The potential mechanism of LDH-A promotion in LUAD progression was explored. LDH-A showed an abnormally high expression in LUAD, which is closely associated with poor prognosis in patients with LUAD. In in vitro experiments, silencing LDH-A expression in LUAD cells could effectively inhibit proliferation, invasion, migration, and colony formation of cancer cells. In in vivo experiments, tumor growth was markedly inhibited by LDH-A silencing in a xenograft model of LUAD. Notably, LDH-A could also promote tumor progression by regulating epithelial–mesenchymal transition (EMT)-related molecules. LDH-A can promote the malignant biological behaviors of LUAD cells, and thus can be a potential target for LUAD treatment.

NCAPG promotes the progression of lung adenocarcinoma via the TGF-β signaling pathway

Cancer Cell International ◽

10.1186/s12935-021-02138-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yun Wu ◽

Ying Lin ◽

Junfan Pan ◽

Xunwei Tu ◽

Yiquan Xu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Cox Regression ◽

Case Fatality ◽

Immunohistochemical Analysis ◽

Abstract Background Lung cancer has the highest case fatality rate among cancers because of uncontrolled proliferation and early metastasis of cancer cells in the lung tissue. This study aimed to clarify the role of the non-SMC condensin I complex, subunit G (NCAPG) in lung adenocarcinoma (LUAD), explore the mechanisms of its progression, and lay the foundation for the search for new biological markers. Methods We analyzed overlapping differentially expressed genes (DEGs) from three datasets; a protein–protein interaction (PPI) network was subsequently constructed and analyzed using Cytoscape. We then selected NCAPG for validation because of its poor prognosis and because it has not been sufficiently studied in the context of LUAD. Immunohistochemical analysis was used to detect the expression of NCAPG in LUAD tissues, and the relationships between NCAPG and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to verify the role of NCAPG in LUAD. Finally, we studied the specific mechanism of action of NCAPG in LUAD. Results Through comprehensive analysis of the GSE43458, GSE75037, and The Cancer Genome Atlas databases, we identified 517 overlapping DEGs. Among them, NCAPG was identified as a hub gene. Immunohistochemical analysis revealed that NCAPG was strongly associated with the clinical stage, M-classification, and N-classification. Univariate and multivariate Cox regression analyses indicated that NCAPG was a prognostic risk factor for LUAD, while the in vitro experiments showed that NCAPG overexpression promoted proliferation, migration, invasion, and epithelial-mesenchymal transition. Furthermore, knockdown of NCAPG inhibited LUAD progression, both in vitro and in vivo. Mechanistically, NCAPG overexpression increased p-Smad2 and p-Smad3 expressions in the transforming growth factor β (TGF-β) signaling pathway. Additionally, rescue experiments indicated that TGF-β signaling pathway inhibitors could restore the effect of NCAPG overexpression in LUAD cells. Conclusions NCAPG may promote proliferation and migration via the TGF-β signaling pathway in LUAD.

ELK1 Promotes Epithelial-Mesenchymal Transition and the Progression of Lung Adenocarcinoma by Upregulating B7-H3

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/2805576 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Ting-ting Yu ◽

Tao Zhang ◽

Fei Su ◽

Ying-long Li ◽

Li Shan ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Epithelial To Mesenchymal Transition ◽

Transcriptional Regulator ◽

Mesenchymal Transition ◽

Poor Patient ◽

Patient Prognosis

In previous studies, we found that B7 homolog 3 (B7-H3) was highly expressed in lung adenocarcinoma (LUAD) and promoted epithelial-to-mesenchymal transition (EMT) of LUAD cells. However, the underlying molecular mechanism is unclear. This study is aimed at evaluating the role of Ets-like protein 1 (ELK1) as a transcriptional regulator of B7-H3 for mediating the development and progression of LUAD in vitro and in vivo. We confirmed that ELK1 is highly expressed in LUAD and is associated with poor patient prognosis. ELK1 was found to promote proliferation, invasion, migration, and EMT of LUAD cells through in vivo and in vitro experiments. In terms of mechanism, ELK1 binds to the B7-H3 promoter region and induces the upregulation of B7-H3 in LUAD. Our data suggest that ELK1 plays an important role in the development of LUAD and could be used as a prognostic marker and therapeutic target for LUAD.

Circ_0000285 regulates proliferation, migration, invasion and apoptosis of osteosarcoma by miR-409-3p/IGFBP3 axis

Cancer Cell International ◽

10.1186/s12935-020-01557-5 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Zhisheng Long ◽

Feipeng Gong ◽

Yuxu Li ◽

Zhiqiang Fan ◽

Jingtang Li

Keyword(s):

Rna Binding ◽

Binding Protein ◽

Animal Experiments ◽

Luciferase Reporter ◽

Circular Rnas ◽

Invasion And Migration ◽

And Migration

Abstract Background Circular RNAs (circRNAs) are important regulators in the pathogenesis of diseases and affects the occurrence and development of diseases. However, the role of circRNAs in osteosarcoma (OS) has not been fully elucidated. Methods The expression of circ_0000285, miR-409-3p and insulin-like growth factor binding protein 3 (IGFBP3) was detected using quantitative real-time PCR (qRT-PCR). The protein level of IGFBP3 was measured using western blot. CCK-8 and colony formation assays were used to determine cell proliferation. Flow cytometry was applied to measure cell cycle and cell apoptosis. Transwell assay was used to assess cell invasion and migration. Dual-luciferase reporter assay and RNA Binding Protein Immunoprecipitation (RIP) assay were performed to determine the relationship among circ_0000285, miR-409-3p and IGFBP3. The animal experiments were performed to determine the function of circ_0000285 in vivo. Results In this study, we found that the expression of circ_0000285 was significantly increased in OS tissues and cells and was enriched in the cytoplasm. Knockdown of circ_0000285 inhibited OS growth in vitro and in vivo. Moreover, miR-409-3p was a target miRNA of circ_0000285 and miR-409-3p targets to IGFBP3 in OS. Besides, circ_0000285 could promote proliferation, migration, invasion and inhibit apoptosis of osteosarcoma by miR-409-3p/IGFBP3 axis. Conclusion In this study, circ_0000285 regulated proliferation, migration, invasion and apoptosis of OS cells by miR-409-3p/IGFBP3 axis, implying that circ_0000285 was a potential target for OS therapy.

Circ-HMGA2 (hsa_circ_0027446) promotes the metastasis and epithelial-mesenchymal transition of lung adenocarcinoma cells through the miR-1236-3p/ZEB1 axis

Cell Death and Disease ◽

10.1038/s41419-021-03601-2 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Zhongjian Yu ◽

Xiongjie Zhu ◽

Ying Li ◽

Min Liang ◽

Meijun Liu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Normal Tissues ◽

Cell Metastasis ◽

Incidence And Mortality ◽

Promotive Effect

AbstractLung adenocarcinoma (LUAD) has high incidence and mortality rates worldwide; however, its detailed molecular pathology remains unclear. Although circRNAs have gradually been identified as molecules that are differentially expressed in tumors and play key roles in tumor progression, their role in LUAD is poorly understood. Through microarray analysis, we obtained the circRNA expression profile of LUAD and found that circ-HMGA2 (hsa_circ_0027446), a novel RNA, is highly expressed in LUAD. The high expression of circ-HMGA2 was further verified in 36 paired LUAD and adjacent normal tissues. Functionally, circ-HMGA2 promoted LUAD cell metastasis in vitro and in vivo. The luciferase reporter assay and FISH results showed that circ-HMGA2 interacts with miR-1236-3p and that miR-1236-3p interacts with ZEB1. In addition, miR-1236-3p was expressed at low levels in LUAD, inhibited LUAD cell metastasis, and suppressed the function of circ-HMGA2. ZEB1 is an EMT-promoting transcription factor. The PCR and WB analysis results showed that circ-HMGA2 promotes both ZEB1 expression and EMT. MiR-1236-3p had the opposite effect, reversing the promotive effect of circ-HMGA2 on EMT. In summary, circ-HMGA2 promotes LUAD cell metastasis through the miR-1236-3p/EMT axis, indicating that it could be a therapeutic target in LUAD.

Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01882-1 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Zizhen Si ◽

Lei Yu ◽

Haoyu Jing ◽

Lun Wu ◽

Xidi Wang

Keyword(s):

Colorectal Cancer ◽

Rna Binding ◽

Xenograft Model ◽

Luciferase Reporter ◽

Cancer Proliferation ◽

Mouse Xenograft ◽

Mouse Xenograft Model

Abstract Background Long non-coding RNAs (lncRNA) are reported to influence colorectal cancer (CRC) progression. Currently, the functions of the lncRNA ZNF561 antisense RNA 1 (ZNF561-AS1) in CRC are unknown. Methods ZNF561-AS1 and SRSF6 expression in CRC patient samples and CRC cell lines was evaluated through TCGA database analysis, western blot along with real-time PCR. SRSF6 expression in CRC cells was also examined upon ZNF561-AS1 depletion or overexpression. Interaction between miR-26a-3p, miR-128-5p, ZNF561-AS1, and SRSF6 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. Small interfering RNA (siRNA) mediated knockdown experiments were performed to assess the role of ZNF561-AS1 and SRSF6 in the proliferative actives and apoptosis rate of CRC cells. A mouse xenograft model was employed to assess tumor growth upon ZNF561-AS1 knockdown and SRSF6 rescue. Results We find that ZNF561-AS1 and SRSF6 were upregulated in CRC patient tissues. ZNF561-AS1 expression was reduced in tissues from treated CRC patients but upregulated in CRC tissues from relapsed patients. SRSF6 expression was suppressed and enhanced by ZNF561-AS1 depletion and overexpression, respectively. Mechanistically, ZNF561-AS1 regulated SRSF6 expression by sponging miR-26a-3p and miR-128-5p. ZNF561-AS1-miR-26a-3p/miR-128-5p-SRSF6 axis was required for CRC proliferation and survival. ZNF561-AS1 knockdown suppressed CRC cell proliferation and triggered apoptosis. ZNF561-AS1 depletion suppressed the growth of tumors in a model of a nude mouse xenograft. Similar observations were made upon SRSF6 depletion. SRSF6 overexpression reversed the inhibitory activities of ZNF561-AS1 in vivo, as well as in vitro. Conclusion In summary, we find that ZNF561-AS1 promotes CRC progression via the miR-26a-3p/miR-128-5p-SRSF6 axis. This study reveals new perspectives into the role of ZNF561-AS1 in CRC.