Epithelial-mesenchymal Transition In Lung Cancer Research Articles

Negative regulation of SH2B3 by SMYD5 controls epithelial-mesenchymal transition in lung cancer

The main cause of death in lung cancer patients is metastasis. Thus, efforts to suppress micrometastasis or distant metastasis in lung cancer, identify therapeutic targets and develop related drugs are ongoing. In this study, we identified SMYD5 as a novel metastasis regulator in lung cancer and found that SMYD5 was overexpressed in lung cancer based on both RNA-sequencing (RNA-seq) analysis results derived from the TCGA portal and immunohistochemical analysis results; knockdown of SMYD5 inhibited cell migration and invasion by changing EMT (epithelial-mesenchymal transition) markers and MMP9 expression in NCI-H1299 and H1703 cell lines. Additionally, SMYD5 knockdown increased SH2B3 expression by decreasing the level of H4K20 trimethylation. Furthermore, in an in vitro EMT system using TGF-β treatment, SMYD5 knockdown resulted in reduced cell migration and invasion in the highly invasive NCI-H1299 and H1703 cell lines. Based on these findings, we propose that SMYD5 could serve as a potential therapeutic target for lung cancer treatment and that cotreatment with an SMYD5 inhibitor and chemotherapy may enhance the therapeutic effect of lung cancer treatment.

NSUN6 Regulates NM23-H1 Expression in an m5C Manner to Affect Epithelial-Mesenchymal Transition in Lung Cancer

Purpose: The expression and regulatory mechanism of NSUN6 in lung cancer are still unclear. Our study explored whether NSUN6 mediates progression of lung cancer by affecting NM23-H1 expression in an m5C-dependent manner. Methods: qRT-PCR, CCK-8, colony formation, transwell, and Western blot analysis were employed to probe the impact of NSUN6 on lung cancer cell proliferation, migration, and epithelial-mesenchymal transition (EMT). RMVar database was utilized to forecast the downstream genes of NSUN6. The mode of interaction between NSUN6 and NM23-H1 was determined by dot blot, luciferase assay, m5C RIP, and cell function assays. The effect of NSUN6 expression on tumor growth was verified in vivo. Results: Expression of NSUN6 was reduced in lung cancer cells, and over-expression of NSUN6 restricted the proliferation of lung cancer cells, migration, and EMT. NSUN6 regulated NM23-H1 expression by modifying the 3′-UTR of NM23-H1 mRNA through m5C and inhibited lung cancer cell proliferation, migration, and EMT. In vivo experiments also showed that over-expression of NSUN6 inhibited the occurrence of lung cancer. Conclusion: NSUN6 regulates NM23-H1 expression in an m5C-dependent manner to affect EMT in lung cancer. Thus, NSUN6 may be considered as a potential therapeutic target for lung cancer.

Impact of KIF4A on Cancer Stem Cells and EMT in Lung Cancer and Glioma

Kinesin family member 4A (KIF4A) belongs to the kinesin 4 subfamily of kinesin-related proteins and is involved in the regulation of chromosome condensation and segregation during mitotic cell division. The expression of KIF4A in various types of cancer, including lung, breast, and colon cancer, has been found to be associated with poor prognosis in cancer patients. However, the exact mechanism by which it promotes tumorigenesis is not yet understood. In osteosarcoma, the expression of KIF4A has been shown to be associated with cancer stem cells (CSCs), whereas in breast cancer, it is not associated with the maintenance of CSCs but regulates the migratory ability of cells. In this light, we identified phenotypic phenomena affecting the malignancy of cancer in lung cancer and glioma, and investigated the mechanisms promoting tumorigenesis. As a result, we demonstrated that KIF4A affected lung cancer stem cells (LCSCs) and glioma stem cells (GSCs) and regulated CSC signaling mechanisms. In addition, the migratory ability of cells was regulated by KIF4A, and epithelial-to-mesenchymal transition (EMT) marker proteins were controlled. KIF4A regulated the expression of the secretory factor plasminogen activator inhibitor-1 (PAI-1), demonstrating that it sustains cancer malignancy through an autocrine loop. Taken together, these findings suggest that KIF4A regulates CSCs and EMT, which are involved in cancer recurrence and metastasis, indicating its potential value as a novel therapeutic target and prognostic marker in lung cancer and glioma.

(−)-Guaiol inhibit epithelial-mesenchymal transition in lung cancer via suppressing M2 macrophages mediated STAT3 signaling pathway

In the context of cancer expansion, epithelial-mesenchymal transition (EMT) plays an essential role in driving invasion and metastasis potential of cancer cells. Tumor-associated macrophages (TAMs)-derived factors involved in the initiation and progression of EMT. We assess the role of M2 macrophage in suppressing lung tumors of a natural compound (−)-Guaiol by using macrophage depleted model. Bone marrow-derived monocytes (BMDMs) were extracted and induced to M2-like phenotype in vitro. The co-culture of M2 macrophage and lung cancer cells was established to observe that inhibition of lung tumor growth by (−)-Guaiol requires presence of macrophages. This suppressed effect of (−)-Guaiol was alleviated when mice macrophage was depleted. The expression of M2-like macrophages was strongly reduced by (−)-Guaiol treated mice, but not the changes of M1-like macrophages. In vitro studies, we demonstrated that (−)-Guaiol suppressed M2 polarization of BMDMs, as well as migration, invasion, and EMT of lung cancer cells in co-culture. M2 macrophage-derived interleukin 10 (IL-10) was investigated as a critical signaling molecule between M2 macrophage and lung cancer cells. We have also verified that the mechanism of (−)-Guaiol inhibiting the EMT process of lung cancer is related to the activation of IL-10-mediated signal transducer and activator of transcription 3 (STAT3). These results suggested that the suppressive effect role of (−)-Guaiol in M2 macrophage promoting EMT of lung cancer, which was associated with inhibition of IL-10 mediated STAT3 signaling pathway.

PRMT5 facilitates angiogenesis and EMT via HIF-1α/VEGFR/Akt signaling axis in lung cancer.

Abnormal angiogenesis is a critical factor in tumor growth and metastasis, and protein arginine methyltransferase 5 (PRMT5), a prominent type II enzyme, is implicated in various human cancers. However, the precise role of PRMT5 in regulating angiogenesis to promote lung cancer cell metastasis and the underlying molecular mechanisms are not fully understood. Here, we show that PRMT5 is overexpressed in lung cancer cells and tissues, and its expression is triggered by hypoxia. Moreover, inhibiting or silencing PRMT5 disrupts the phosphorylation of the VEGFR/Akt/eNOS angiogenic signaling pathway, NOS activity, and NO production. Additionally, inhibiting PRMT5 activity reduces HIF-1α expression and stability, resulting in the down-regulation of the VEGF/VEGFR signaling pathway. Our findings indicate that PRMT5 promotes lung cancer epithelial-mesenchymal transition (EMT), which might be possibly through controlling the HIF-1α/VEGFR/Akt/eNOS signaling axis. Our study provides compelling evidence of the close association between PRMT5 and angiogenesis/EMT and highlights the potential of targeting PRMT5 activity as a promising therapeutic approach for treating lung cancer with abnormal angiogenesis.

A data-driven optimization method for coarse-graining gene regulatory networks

One major challenge in systems biology is to understand how various genes in a gene regulatory network (GRN) collectively perform their functions and control network dynamics. This task becomes extremely hard to tackle in the case of large networks with hundreds of genes and edges, many of which have redundant regulatory roles and functions. The existing methods for model reduction usually require the detailed mathematical description of dynamical systems and their corresponding kinetic parameters, which are often not available. Here, we present a data-driven method for coarse-graining large GRNs, named SacoGraci, using ensemble-based mathematical modeling, dimensionality reduction, and gene circuit optimization by Markov Chain Monte Carlo methods. SacoGraci requires network topology as the only input and is robust against errors in GRNs. We benchmark and demonstrate its usage with synthetic, literature-based, and bioinformatics-derived GRNs. We hope SacoGraci will enhance our ability to model the gene regulation of complex biological systems.

Proteasome inhibitor immunotherapy for the epithelial to mesenchymal transition: assessing the A549 lung cancer cell microenvironment and the role of M1, M2a and M2c 'hydrocortisone-polarised' macrophages.

Lung cancer is a leading cause of cancer-related deaths, primarily as a result of metastases. In this metastasis, the epithelial-to-mesenchymal transition (EMT) is essential. Interaction with the cancer cell microenvironment is primarily dependent on M1- and M2-polarized macrophage. In this study, we revealed the EMT-associated activity of M1, M2a and M2c macrophages in A549 lung cancer cells. We established a co-culture model of A549 lung cancer cells utilizing THP-1-derived M1/M2 polarised macrophages to explore the involvement of macrophages in the immune response, apoptosis, and EMT in lung cancer. Although multiple polarising agents are routinely used for M1 and M2 conversion, we assessed a new possible polarising agent, hydrocortisone. M1 increased A549 cell sensitivity to proteasome inhibitors and decreased A549 cell viability by inducing apoptosis. EMT was induced in the presence of M2c macrophages in A549 cells by the levels of vimentin, fibronectin, E-cadherin, NF-kB, CCL-17. We also revealed the antiproliferative effects of bortezomib and ixazomib on A549 cells in both 2D and 3D cultures. Our findings could help develop an immunotherapeutic strategy by shedding light on a previously undiscovered part of the EMT pathway. Furthermore, additional investigation may reveal that polarising tumour-associated macrophages to M1 and eliminating the M2a or particularly the M2c subtype are effective anti-cancer strategies.

Epithelial-Mesenchymal Transition-Inducing Factors Involved in the Progression of Lung Cancers.

Although there have been advances in cancer therapy and surgical improvement, lung cancer has the lowest survival rate (19%) at all stages. This is because most patients are diagnosed with concurrent metastasis, which occurs due to numerous related reasons. Especially, lung cancer is one of the most common and malignant cancers in the world. Although there are advanced therapeutic strategies, lung cancer remains one of the main causes of cancer death. Recent work has proposed that epithelial-mesenchymal transition (EMT) is the main cause of metastasis in most cases of human cancers including lung cancer. EMT involves the conversion of epithelial cells, wherein the cells lose their epithelial abilities and become mesenchymal cells involved in embryonic development, such as gastrulation and neural crest formation. In addition, recent research has indicated that EMT contributes to altering the cancer cells into cancer stem cells (CSCs). Although EMT is important in the developmental stages, this process also activates lung cancer progression, including complicated and diverse signaling pathways. Despite the numerous investigations on signaling pathways involved in the progression of lung cancer, this malignancy is considered critical for treatment. EMT in lung cancer involves many transcription factors and inducers, for example, Snail, TWIST, and ZEB are the master regulators of EMT. EMT-related factors and signaling pathways are involved in the progression of lung cancer, proposing new approaches to lung cancer therapy. In the current review, we highlight the signaling pathways implicated in lung cancer and elucidate the correlation of these pathways, indicating new insights to treat lung cancer and other malignancies.

FBI-1 inhibits epithelial-to-mesenchymal transition, migration, and invasion in lung adenocarcinoma A549 cells by downregulating transforming growth factor-β1 signaling pathway.

The factor binding inducer of short transcripts-1 (FBI-1) is a POZ-domain Kruppel-like (POK) family of transcription factors and is known as a proto-oncogene or tumor suppressor in various carcinomas. However, the role of FBI-1 on epithelial-to-mesenchymal transition(EMT) and invasiveness in lung cancer remains unknown. Preliminarily, clinical data such as tissue microarray, Kaplan-Meier, and Oncomine were analyzed to confirm the correlation between lung cancer metastasis and FBI-1. To investigate the function of FBI-1 in EMTin lung cancer, EMT was measured in FBI-1-deficient or FBI-1-overexpressing cells. FBI-1 showed decreased expression in tumors metastasized to lymph nodes than in the primary tumor. In addition, it was also associated with improved survival rates of lung cancer patients. FBI-1 knockdown improved E-to-N-cadherin switching, migration, and invasion in A549 cells, similar to the initiation of EMT stimulated by transforming growth factor- β1 (TGF-β1). In contrast, overexpression of FBI-1 inhibited the transcription and activation of Smad2, thereby interfering with EMT, despite stimulation by TGF-β1. These results suggest that FBI-1 plays a negative role in EMT in lung cancer via the TGF-β1 signaling pathway, implying its use as a new potential therapeutic target and diagnostic indicator for early stage of lung cancer metastasis.

LASP1 Induces Epithelial-Mesenchymal Transition in Lung Cancer through the TGF-β1/Smad/Snail Pathway.

Background LIM and SH3 domain protein 1 (LASP1), highly expressed in a variety of tumors, is considered as a novel tumor metastasis biomarker. However, it is unknown which signaling pathway works and how the signal transduces into cell nucleus to drive tumor progression by LASP1. The aim of this study is to explore the essential role of LASP1 in TGF-β1-induced epithelial-mesenchymal transition (EMT) in lung cancer cells. Methods The gene and protein levels of LASP-1 were successfully silenced or overexpressed by LASP-1 shRNA lentivirus or pcDNA in TGF-β1-treated lung cancer cell lines, respectively. Then, the cells were developed EMT by TGF-β1. The cell abilities of invasion, migration, and proliferation were measured using Transwell invasion assay, wound healing assay, and MTT assay, respectively. Western blotting was used to observe the protein levels of EMT-associated molecules, including N-cadherin, vimentin, and E-cadherin, and the key molecules in the TGF-β1/Smad/Snail signaling pathway, including pSmad2 and Smad2, pSmad3 and Smad3, and Smad7 in cell lysates, as well as Snail1, pSmad2, and pSmad3 in the nucleus. Results TGF-β1 induced higher LASP1 expression. LASP1 silence and overexpression blunted or promoted cell invasion, migration, and proliferation upon TGF-β1 stimulation. LASP1 also regulated the expression of vimentin, N-cadherin, and E-cadherin in TGF-β1-treated cells. Activity of key Smad proteins (pSmad2 and pSmad3) and protein level of Smad7 were markedly regulated through LASP1. Furthermore, LASP1 affected the nuclear localizations of pSmad2, pSmad3, and Snail1. Conclusion This study reveals that LASP1 regulates the TGF-β1/Smad/Snail signaling pathway and EMT markers and features, involving in key signal molecules and their nuclear levels. Therefore, LASP1 might be a drug target in lung cancer.

Abstract 2883: Theranostics nanoparticles targeting to metastatic non small cell lung cancer

Abstract Non-small-cell lung cancer (NSCLC) accounts for one of the most deadly cancers due to metastasis after therapy. Cancer metastasis usually results from epithelial-to-mesenchymal transition (EMT), and metabolic disorder is a key mediator of lung cancer EMT. The linkage between metabolic disorder and NSCLC EMT is still unclear. Using in silico analysis, C4ST1, a key enzyme of glycosaminoglycan synthesis pathway was up-regulation in mesenchymal type NSCLC cells. C4ST1 catalyzes chondroitin sulfate A (CsA) formation. We found both C4ST1 and CsA were up-regulation in mesenchymal type NSCLC cells. Not only C4ST1 overexpression but also CsA treatments changed NSCLC EMT balance and decreased the transcriptional activity on CDH1 promoter region. Furthermore, both treatments could promote in vitro NSCLC migration and invasion abilities in the epithelial type NSCLC cells. Up-regulation of C4ST1 cells also promoted lung cancer metastasis. Moreover, we used CsA binding peptide as a targeting ligands of metastatic NSCLC cells on theranostics nanoparticles. In summary, this study finds key gene in NSCLC EMT. Up-regulation of C4ST1 promotes NSCLC EMT and cell surface CsA content which may provide a novel theranostics niche on metastatic NSCLC cells. Citation Format: LI-JIE LI, Ming-Hsien Chan, Wei-Min Chang, Michael Hsiao. Theranostics nanoparticles targeting to metastatic non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2883.

Interleukin-17A mediates tobacco smoke-induced lung cancer epithelial-mesenchymal transition through transcriptional regulation of ΔNp63α on miR-19.

Interleukin-17A (IL-17A) is an essential inflammatory cytokine in the progress of carcinogenesis. Tobacco smoke (TS) is a major risk factor of lung cancer that influences epithelial-mesenchymal transition (EMT) process. However, the potential mechanism by which IL-17A mediates the progression of lung cancer in TS-induced EMT remains elusive. In the present study, it was revealed that the IL-17A level was elevated in lung cancer tissues, especially in tumor tissues of cases with experience of smoking, and a higher IL-17A level was correlated with induction of EMT in those specimens. Moreover, the expression of ΔNp63α was increased in IL-17A-stimulated lung cancer cells. ΔNp63α functioned as a key oncogene that bound to the miR-17-92 cluster promoter and transcriptionally increased the expression of miR-19 in lung cancer cells. Overexpression of miR-19 promoted EMT in lung cancer with downregulation of E-cadherin and upregulation of N-cadherin, while its inhibition suppressed EMT. Finally, the upregulated levels of IL-17A, ΔNp63α, and miR-19 along with the alteration of EMT-associated biomarkers were found in lung tissues of TS-exposed mice. Taken together, the abovementioned results suggest that IL-17A increases ΔNp63α expression, transcriptionally elevates miR-19 expression, and promotes TS-induced EMT in lung cancer. These findings may provide a new insight for the identification of therapeutic targets for lung cancer.

TAp63α Is Involved in Tobacco Smoke-Induced Lung Cancer EMT and the Anti-cancer Activity of Curcumin via miR-19 Transcriptional Suppression.

As a key risk factor for lung cancer, tobacco smoke (TS) influences several cellular processes, including epithelial-mesenchymal transition (EMT). TAp63α is a crucial transcription factor involved in tumor progression. The present study was designed to investigate the potential role and underlying mechanisms of TAp63α in TS-induced lung cancer EMT. We found that compared to normal tissues, the tumor tissues collected from lung cancer patients showed a lower level of TAp63α expression, along with downregulated E-cadherin expression and upregulated Vimentin expression. Results of treatment with TAp63α and TAp63α siRNA as well as with tumor growth factor-β (TGF-β) showed that TAp63α acted as a tumor suppressor gene, and its upregulated expression suppressed lung cancer EMT. Significantly, TS exposure altered expression of EMT-related markers, enhanced cell migratory and invasive capacities, and decreased the TAp63α expression level in lung cancer cells. Overexpression of TAp63α significantly alleviated TS-stimulated lung cancer EMT. Mechanistically, TAp63α expression transcriptionally reduced the miR-19 level, which resulted in the suppression of lung cancer EMT. Additionally, as a natural compound possessing anti-cancer effects, curcumin inhibited TS-induced lung cancer EMT by increasing TAp63α expression and reducing miR-19 expression. Collectively, our results indicate that TAp63α inhibits TS-induced lung cancer EMT via transcriptionally suppressing miR-19 and the inhibitory effect of TAp63α on miR-19 mediates the anti-cancer action of curcumin. These findings provide new insights into novel targets for lung cancer prevention.

Crosstalk of Long Non-coding RNAs and EMT: Searching the Missing Pieces of an Incomplete Puzzle for Lung Cancer Therapy

Lung cancer is considered to be the first place among the cancer-related deaths worldwide and demands novel strategies in the treatment of this life-threatening disorder. The aim of this review is to explore regulation of epithelial-to-mesenchymal transition (EMT) by long non-coding RNAs (lncRNAs) in lung cancer. LncRNAs can be considered as potential factors for targeting in cancer therapy, since they regulate a bunch of biological processes, e.g. cell proliferation, differentiation and apoptosis. The abnormal expression of lncRNAs occurs in different cancer cells. On the other hand, epithelial-to-mesenchymal transition (EMT) is a critical mechanism participating in migration and metastasis of cancer cells. Different databases including Googlescholar, Pubmed and Sciencedirect were used for collecting articles using keywords such as "LncRNA", "EMT", and "Lung cancer". There are tumor-suppressing lncRNAs that can suppress EMT and metastasis of lung cancer cells. Expression of such lncRNAs undergoes down-regulation in lung cancer progression and restoring their expression is of importance in suppressing lung cancer migration. There are tumor-promoting lncRNAs triggering EMT in lung cancer and enhancing their migration. LncRNAs are potential regulators of EMT in lung cancer, and targeting them, both pharmacologically and genetically, can be of importance in controlling migration of lung cancer cells.

Quantitative Analysis of Actin Cytoskeleton's Morphological Changes during EMT in Lung Cancer and Pre-Cancer Cell Lines

Lung cancer, a highly metastatic disease, is the world's leading cause of cancer death. Epithelial to mesenchymal Transition (EMT), a key element of the metastatic process in lung cancer, is accompanied by corresponding changes in cellular mechanical properties, principally resulting from actin stress fiber formation. The details of the micro and macro rearrangement processes involved in this cytoskeletal reorganization is not yet fully understood. Using standard transfection/ staining and imaging protocols, we identified a novel cellular phenotype during the EMT process. This interim phenotype was characterized by a disoriented (nest-like) stress fiber arrangement in contrast to the highly aligned (semi-parallel) cytoskeleton in the final mesenchymal cell. The formation of this nest-like pattern was consistent amongst different EMT induction techniques and concentrations. Drug treatment assays suggested that inhibition of the PI3K-Akt signaling pathway prevents the formation of the final semi-parallel phenotype from the nest-like phenotype. To quantify the actin cytoskeleton remodeling, we utilized computational extraction of actin stress fibers from wide-field and confocal microscopic images. We developed a computational tool that extracts the actin stress fibers as straight lines, quantified through their locations, lengths and relative orientations. This tool further statistically processes the orientation information to generate the Orientational Order Parameter (OOP), which serves as a figure of merit to classify cells into nest-like cytoskeletal phenotype and the semi-parallel cytoskeletal phenotype. This figure of merit could possibly be utilized for other cytoskeletal remodeling processes such as fibrosis, apoptosis, cell division and migration.

Ethacrynic acid, a loop diuretic, suppresses epithelial-mesenchymal transition of A549 lung cancer cells via blocking of NDP-induced WNT signaling

Lung cancer is one of the leading causes of death in cancer patients. Epithelial-mesenchymal transition (EMT) plays an important role in lung cancer progression. Therefore, for lung cancer treatment, it is crucial to find substances that inhibit EMT. Ethacrynic acid (ECA) is a diuretic that inhibits cellular ion flux and exerts anticancer effects. However, the effects of ECA on EMT in lung cancer remain unclear. We examined the effects of ECA on sphingosylphosphorylcholine (SPC) or TGF-β1-induced EMT process in A549 and H1299 cells via reverse transcription polymerase chain reaction and Western blotting. We found that ECA inhibited SPC-induced EMT and SPC-induced WNT signalling in EMT. We observed that SPC induces the expression of NDP [Norrie disease protein] and WNT-2, whereas ECA suppressed their expression. SPC-induced WNT activation, EMT, migration, and invasion were suppressed by NDP small-interfering RNA (siNDP), but NDP overexpression (pNDP) enhanced these events in A549 and H1299 cells. Accordingly, NDP expression may influence lung cancer prognosis. In summary, our results revealed that ECA inhibited SPC or TGF-β1-induced EMT in A549 and H1299 lung cancer cells by downregulating NDP expression and inhibiting WNT activation. Therefore, ECA might be a new drug candidate for lung cancer treatment.

158 Poster - Epigenetic regulation of epithelial-to-mesenchymal transition as a captain of journey of cancer from lung to brain

Background: There have been many studies for epithelial-to-mesenchymal transition (EMT) of the cancer, especially focused on the important transcriptional factors. Recently epigenetic mechanisms, including histone modification have been comprehensively studied for establishing the role on the prohibiting metastasis of cancer cell. The objective of presenting study is to investigate the epigenetic role of histone lysine methylation/demethylation on the regulating expression of the transcriptional factors of EMT in lung cancer and brain metastasis.

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer.

Radiation therapy is a common and acceptable approach for lung cancer. Although the benefit of ionizing radiation (IR) is well-established, cancer cells can still survive via pro-survival and metastasis signaling pathways. Ras related C3 botulinum toxin substrate1 (RAC1), a member of Rho family GTPases, plays important roles in cell migration and survival. In the present study, we investigated the effects of RAC1 on the survival of lung cancer cells treated with irradiation. The results showed RAC1 is overexpressed in lung cancer cells and promoted cell proliferation and survival. Furthermore, IR induced RAC1 expression and activity via the activation of PI3K/AKT signaling pathway, and then enhancing cell proliferation, survival, migration and metastasis and increasing levels of epithelial-to-mesenchymal transition (EMT) markers, which facilitated the cell survival and invasive phenotypes. In addition, overexpression of RAC1 attenuated the efficacy of irradiation, while inhibition of RAC1 enhanced sensitivity of irradiation in xenograft tumors in vivo. Collectively, we further found that RAC1 enhanced radioresistance by promoting EMT via targeting the PAK1-LIMK1-Cofilins signaling in lung cancer. Our finding provides the evidences to explore RAC1 as a therapeutic target for radioresistant lung cancer cells.

Knockdown of Linc00511 inhibits TGF-β-induced cell migration and invasion by suppressing epithelial-mesenchymal transition and down-regulating MMPs expression

Epithelial mesenchymal transition (EMT) is a critical step in cancer metastasis. Some evidences have been provided to verify up-regulation of linc00511 in multiple cancers and oncogenic roles during cancer malignant process. But, the roles of linc00511 on the metastasis of lung cancer are still largely unclear. Our study aims to reveal the functional effects of linc00511 on TGF-β1-induced EMT in lung cancer. Our results showed that knockdown of linc00511 significantly inhibited TGF-β1-induced migration and invasion and down-regulated the mRNA and protein levels of MMP2, MMP9 and MMP12 in TGF-β1 treated SPCA1 and H1975 cells. Also, western blotting results showed that inhibition of linc00511 remarkably suppressed TGF-β1-induced N-cadherin, Vimentin and snail and increased E-cadherin expression in SPCA1 and H1975 cells. Noteworthy, we further found that inhibition of linc00511 could down-regulate TGF-β1-induced ZEB2 mRNA and protein levels by sponging miR-183-5p in SPCA1 and H1975 cells. Taken together, our findings suggested knockdown linc00511 suppressed TGF-β1-induced migration and invasion via inhibiting EMT and MMPs in lung cancer cells.

MiRNAs and LncRNAs: Dual Roles in TGF-β Signaling-Regulated Metastasis in Lung Cancer.

Lung cancer is one of the most malignant cancers around the world, with high morbidity and mortality. Metastasis is the leading cause of lung cancer deaths and treatment failure. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs), two groups of small non-coding RNAs (nc-RNAs), are confirmed to be lung cancer oncogenes or suppressors. Transforming growth factor-β (TGF-β) critically regulates lung cancer metastasis. In this review, we summarize the dual roles of miRNAs and lncRNAs in TGF-β signaling-regulated lung cancer epithelial-mesenchymal transition (EMT), invasion, migration, stemness, and metastasis. In addition, lncRNAs, competing endogenous RNAs (ceRNAs), and circular RNAs (circRNAs) can act as miRNA sponges to suppress miRNAs, thereby mediating TGF-β signaling-regulated lung cancer invasion, migration, and metastasis. Through this review, we hope to cast light on the regulatory mechanisms of miRNAs and lncRNAs in TGF-β signaling-regulated lung cancer metastasis and provide new insights for lung cancer treatment.