Invasion Of Lung Adenocarcinoma Cells Research Articles

Restoration of KLF4 Inhibits Invasion and Metastases of Lung Adenocarcinoma through Suppressing MMP2.

Background: KLF4 is a zin-finger transcription factor that plays roles in differentiation, development, and proliferation. Recent studies show that KLF4 is involved in tumorigenesis and somatic cells reprogramming. Metastasis is the primary cause of death in patients with lung cancer, and its biological mechanisms are poorly understood.Goals: In this study, we aim to explore the expression pattern and biological function of KLF4 in lung adenocarcinoma.Methods: We determined KLF4 in lung adenocarcinoma tissue and cell lines, using immunohistochemistry and western blotting. And we further analyzed the correlation between KLF4 expression and clinicopathologic parameters. We restored KLF4 expression and studied its effect on lung adenocarcinoma cells in vivo and in vitro. Luciferase assay was used to study impact of KLF4 on activity of MMP2 promoter.Results: KLF4 is dramatically down-regulated in lung adenocarcinoma tissue and cell lines. Promoter methylation contributes to the down-regulation of KLF4. Down-regulation of KLF4 in lung adenocarcinoma tissue is significantly associated with reduced survival time. Restoration of KLF4 inhibits migration and invasion of lung adenocarcinoma cells in vitro. Metastases to lungs significantly decrease in mice intravenously injected with tumor cells overexpressing KLF4. KLF4 inhibits invasion and metastasis via suppressing MMP2 promoter activity.Conclusion: The ability of KLF4 to inhibit migration, invasion, and metastasis of lung tumor cells indicates a potential role of KLF4 as therapeutic target in lung adenocarcinoma. KLF4 might be utilized as a favorable biomarker for prognosis of lung adenocarcinoma patients.

Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

Our previous study revealed that Ku80 was overexpressed in lung cancer tissues and hsa-miR-623 regulated the Ku80 expression; however, the detailed function of hsa-miR-623 in lung cancer was unclear. We identified that hsa-miR-623 bound to the 3'-UTR of Ku80 mRNA, thus significantly decreasing Ku80 expression in lung adenocarcinoma cells. Hsa-miR-623 was downregulated in lung adenocarcinoma tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Downregulation of hsa-miR-623 was associated with poor clinical outcomes of lung adenocarcinoma patients. Hsa-miR-623 suppressed lung adenocarcinoma cell proliferation, clonogenicity, migration and invasion in vitro. Hsa-miR-623 inhibited xenografts growth and metastasis of lung adenocarcinoma in vivo. Ku80 knockdown in lung adenocarcinoma cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-623 overexpression. Further, hsa-miR-623 overexpression decreased matrix metalloproteinase-2 (MMP-2) and MMP-9 expression levels, with decreased ERK/JNK phosphorylation. Inhibition of hsa-miR-623 or overexpression of Ku80 promoted lung adenocarcinoma cell invasion, activated ERK/JNK phosphorylation and increased MMP-2/9 expressions, which could be reversed by ERK kinase inhibitor or JNK kinase inhibitor. In summary, our results showed that hsa-miR-623 was downregulated in lung adenocarcinoma and suppressed the invasion and metastasis targeting Ku80 through ERK/JNK inactivation mediated downregulation of MMP-2/9. These findings reveal that hsa-miR-623 may serve as an important therapeutic target in lung cancer therapy.

BRCA1-associated protein 1 deficiency in lung adenocarcinoma predicts poor outcome and increased tumor invasion.

BackgroundThe major pathological type of non-small cell lung cancer is lung adenocarcinoma (LAC), which has a poor prognosis. BRCA1-associated protein-1 (BAP1) is a newly identified tumor suppressor that regulates a number of cellular functions in somatic malignancies. However, the impact of BAP1 expression in LAC has not been investigated.MethodsA total of 112 cases of LAC and 101 cases of non-neoplastic lung diseases were included in this study. The study focused on BAP1 expression in lung tissues and its relationship to patients’ clinical and pathological features. BAP1 expression was detected by immunohistochemistry. A human LAC cell line NCI-H1299 was transfected with lipofectamine p3xFLAG-BAP1. BAP1 gene expression was silenced in another LAC cell line NCI-H1650, in order to test the inhibitory effect of BAP1 on cell migration and invasion, as well as cell cycle regulation.ResultsBAP1 expression showed a negative correlation with tumorigenesis of LAC (p <0.001) and lymph node metastasis (p = 0.010). High expression of BAP1 predicted longer disease free survival (p = 0.040) and overall survival (p = 0.021) of LAC patients. In functional assays, BAP1 was found to inhibit the migration and invasion of LAC cells, and promoted their apoptosis and necrosis.ConclusionsWe identify BAP1 as a LAC precursor as well as a robust prognostic indicator in LAC patients. This study provides in vitro rationale for the further investigation of BAP1 in preclinical studies.

Elevated expression of WWP2 in human lung adenocarcinoma and its effect on migration and invasion

Lung cancer has been a hot area of research because of its high incidence and mortality. In this study, WWP2, an E3 ubiquitin ligase, is proposed to be an oncoprotein contributing to lung tumorigenesis. We attempted to determine if WWP2 gene expression is correlated with the development of human lung adenocarcinoma. Real-time PCR and western blotting were used to detect the expression of WWP2 in 65 paired lung adenocarcinoma and adjacent normal lung tissues. We found that WWP2 expression was elevated in lung adenocarcinoma tissues and was correlated with the tumor differentiation stage, TNM stage and presence of lymph node metastasis. We performed CCK-8 and colony formation assays and found that down-regulation of WWP2 inhibited proliferation in A549 and SPC-A-1 cells. A wound healing assay and trans-well invasion assays showed that down-regulation of WWP2 inhibited the migration and invasion of lung adenocarcinoma cells. It could be predicted from these data that elevated expression of WWP2 may play a role in facilitating the development of lung adenocarcinoma.

Expression of ATP binding cassette E1 enhances viability and invasiveness of lung adenocarcinoma cells invitro.

ATP binding cassette E1 (ABCE1), a member of the family of ATP binding cassette transporters, has initially emerged as an RNaseL inhibitor. As a highly conserved protein, it is involved in capsid assembly and translation processes of the human immunodeficiency virus as well as in tumor development and progression. Studies have shown that ABCE1 protein was overexpressed in lung carcinoma tissues and metastatic lymph nodes compared to normal lung tissues. However, little is known about the roles of ABCE1 in lung cancer. The present study investigated the biological effects of vector-mediated ABCE1 overexpression in lung cancer cells invitro and examined the underlying molecular mechanisms. Overexpression of ABCE1 in the LTEP‑a-2 lung adenocarcinoma cell line was achieved by transfection with a plasmid containing full‑length ABCE1 cDNA. The ectopic expression of ABCE1 was shown to promote the viability and invasive capacity of lung cancer cells, and to in reduce p27 expression. However, overexpression of ABCE1 did not significantly affect the cell cycle distribution. In conclusion, the present study suggested that ABCE1 promotes the growth, invasion and metastasis of lung adenocarcinoma cells and may represent a potential biomarker and therapeutic target for lung cancer.

(-)-β-hydrastine suppresses the proliferation and invasion of human lung adenocarcinoma cells by inhibiting PAK4 kinase activity.

(-)-β-hydrastine is one of the main active components of the medicinal plant, Hydrastis canadensis, which is used in many dietary supplements intended to enhance the immune system. However, whether (-)-β-hydrastine affects the tumor signaling pathway remains unexplored. In the present study, we found that (-)-β-hydrastine inhibited the kinase activity of p21-activated kinase 4 (PAK4), which is involved in the regulation of cytoskeletal reorganization, cell proliferation, gene transcription, oncogenic transformation and cell invasion. In the present study, (-)-β-hydrastine suppressed lung adenocarcinoma cell proliferation by inhibiting expression of cyclin D1/D3 and CDK2/4/6, leading to cell cycle arrest at the G1 phase, in a PAK4 kinase-dependent manner. Moreover, inhibition of PAK4 kinase activity by (-)-β-hydrastine also promoted the early apoptosis of lung adenocarcinoma cells through the mitochondrial apoptosis pathway. In addition, (-)-β-hydrastine significantly suppressed the migration and invasion of human lung adenocarcinoma cells in conjunction with concomitant blockage of the PAK4/LIMK1/cofilin, PAK4/SCG10 and PAK4/MMP2 pathways. All of these data indicate that (-)-β-hydrastine, as a novel PAK4 inhibitor, suppresses the proliferation and invasion of lung adenocarcinoma cells. Taken together, these results provide novel insight into the development of a PAK4 kinase inhibitor and a potential therapeutic strategy for lung cancer.

DACH1 inhibits the proliferation and invasion of lung adenocarcinoma through the downregulation of peroxiredoxin 3.

In this study, we found the expression of Dachshund 1 (DACH1) is downregulated while peroxiredoxin 3 (PRX3) upregulated in both lung adenocarcinoma tissues and cells. Transfection of DACH1 can significantly downregulate PRX3 expression in targeting lung adenocarcinoma cells. Further experimental results demonstrated the evidence that overexpression of DACH1 resulted in significant retardation of in vitro proliferation and invasion of lung adenocarcinoma cells. Direct upregulation of PRX3 by co-transfection of PRX3 messenger RNA (mRNA) can prevent the above alteration caused by DACH1 transfection. Besides, lower DACH1 expression significantly correlated with tumor diameter and tumor invasion in all the 36 patients diagnosed with lung adenocarcinoma in our hospital during the past months. In conclusion, DACH1 can inhibit the proliferation and invasion of lung adenocarcinoma through the downregulation of PRX3. Decreased expression of DACH1 is involved in the initiation and development of lung cancer, which might be an adverse prognostic factor of lung adenocarcinoma.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-016-4811-x) contains supplementary material, which is available to authorized users.

TROP2 overexpression promotes proliferation and invasion of lung adenocarcinoma cells

Recent studies suggest that the human trophoblast cell-surface antigen TROP2 is highly expressed in a number of tumours and is correlated with poor prognosis. However, its role in non-small cell lung carcinoma (NSCLC) remains largely unknown. Here we examined TROP2 expression by immunohistochemistry in a series of 68 patients with adenocarcinoma (ADC). We found significantly elevated TROP2 expression in ADC tissues compared with normal lung tissues (P < 0.05), and TROP2 overexpression was significantly associated with TNM (tumour, node, metastasis) stage (P = 0.012), lymph node metastasis (P = 0.038), and histologic grade (P = 0.013). Kaplan–Meier survival analysis revealed that high TROP2 expression correlated with poor prognosis (P = 0.046). Multivariate analysis revealed that TROP2 expression was an independent prognostic marker for overall survival of ADC patients. Moreover, TROP2 overexpression enhanced cell proliferation, migration, and invasion in the NSCLC cell line A549, whereas knockdown of TROP2 induced apoptosis and impaired proliferation, migration, and invasion in the PC-9 cells. Altogether, our data suggest that TROP2 plays an important role in promoting ADC and may represent a novel prognostic biomarker and therapeutic target for the disease.

Clinically relevant concentrations of lidocaine and ropivacaine inhibit TNFα-induced invasion of lung adenocarcinoma cells in vitro by blocking the activation of Akt and focal adhesion kinase

Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells. NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml(-1)) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed. Ropivacaine (1 nM-100 μM) and lidocaine (1-100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10(-6) M for lidocaine; IC50=1.52×10(-10) M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM). At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasis.

MiR-373-3p Promotes Invasion and Metastasis of Lung Adenocarcinoma Cells

背景与目的肺癌位居全球癌症相关死亡率的首位，其中肿瘤转移是导致肺癌患者死亡的主要原因，研究表明miR-373与多种肿瘤细胞的侵袭转移有密切关系。本研究旨在探讨miR-373-3p在非小细胞肺癌(non-small cell lung cancer, NSCLC)中的表达情况及其对肺腺癌细胞侵袭转移能力的影响。方法利用qRT-PCR法检测miR-373-3p在NSCLC组织和肺腺癌细胞株中的表达。瞬时转染hsa-miR-373-3p的mimics和inhibitor至肺腺癌H1299和A549细胞株中，利用Transwell小室检测转染后肺腺癌细胞侵袭转移能力的改变，Western blot检测转染后肺腺癌细胞中基质金属蛋白酶-9(matrix metalloproteinase-9, MMP-9)及MMP-14蛋白水平的改变。结果miR-373-3p在51例NSCLC组织和5种肺腺癌细胞株中均明显高表达。在miR-373-3p低表达的H1299细胞中过表达miR-373-3p，细胞的侵袭转移能力明显提高，同时MMP-9及MMP-14的表达上调；在miR-373-3p高表达的A549细胞中抑制miR-373-3p表达，细胞的侵袭转移能力下降，并且下调MMP-9和MMP-14的表达。结论miR-373-3p可能通过正向调节MMP-9、MMP-14的表达而促进肺腺癌细胞的侵袭转移能力。

Upregulation of SOX9 promotes cell proliferation, migration and invasion in lung adenocarcinoma.

Sex determining region Y-box 9 (SOX9) is an important transcription factor in development and has been implicated in several types of cancer. Although the association between upregulation of SOX9 and lung adenocarcinoma (ADC) has been reported previously, the role of SOX9 in the proliferation, migration and invasion of cancer cells remains unclear. Therefore, in the present study, SOX9 expression was detected in 163 human lung adenocarcinoma tissues by immunohistochemistry and western blotting. It was found that the SOX9 protein was over-expressed in the majority of lung adenocarcinoma. The full-length human SOX9 plasmid was then transfected into the lung ADC A549 cell line. An MTT assay was used to investigate the role of SOX9 in cell proliferation. Scratch and extracellular matrix cell invasion assays were performed to investigate whether SOX9 promotes the migration and invasion of lung ADC cells. The results revealed that ectopic overexpression of SOX9 in the lung adenocarcinoma cell line resulted in a marked increase in cell proliferation, migration and invasion. Accordingly, knockdown of SOX9 by RNA interference resulted in the inhibition of cell growth, migration and invasion. The present data indicate that SOX9 may act as a novel marker for lung adenocarcinoma and perform an important role in cell proliferation, migration and invasion.

USP22 promotes tumor progression and induces epithelial-mesenchymal transition in lung adenocarcinoma.

Our previous study showed that USP22 as an oncogene may mediate cancer development and progression in NSCLC, but the underlying molecular mechanism remains uncharacterized. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in migration and invasion of the tumor cells. Thus, this study aims to determine the clinical significance and the possible roles of USP22 in EMT and progression of lung adenocarcinoma. Immunohistochemistry was used to determine the expression of USP22 in clinical samples. The clinical correlations and prognostic significance of the aberrantly expressed proteins were evaluated by statistical analysis. Moreover, we evaluated whether USP22 could induce EMT in cultured lung cancer cells. The USP22 expression was positive in 76.03% of specimens and was correlated with advanced clinicopathologic classifications (differentiation, T and AJCC stages) and TGF-β1 expression (p=0.008). Multivariate Cox regression analysis revealed that USP22 expression level was an independent prognostic factor for both overall survival and disease-free survival (HR, 2.060; p=0.013 and HR, 1.993; p=0.016). In vitro study revealed that USP22 can regulate proliferation and invasive properties, and induce EMT of lung adenocarcinoma cells. Moreover, USP22 may up-regulate TGF-β1 expression. Our data indicated that USP22 may promote lung adenocarcinoma cell invasion by the induction of EMT.

Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells.

Matrix metalloproteinase-12 (MMP12) is involved in many pathological processes including cancer. The expression and function of MMP12 in lung adenocarcinoma (LAC) remain unclear. The present study aimed to investigate the correlation of MMP12 expression with LAC patients and clarify its role in growth and invasion of LAC cells. The expression of MMP12 in human LAC was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was used for observing the effects of lentiviral vector-mediated MMP12 shRNA (shMMP12) on cell growth and invasion in LAC cell lines (A549), indicated by MTT and Transwell assays. We found that the expression of MMP12 protein was significantly increased in LAC tissues compared with that in adjacent non-cancerous tissues (ANCT) (57.69% vs. 32.69%, P = 0.019), and was closely correlated with the pathological stage and lymph node metastasis of LAC patients (P = 0.01; P = 0.003). Knockdown of MMP12 inhibited proliferation and invasion of LAC cells followed by the downregulation of proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF). In conclusion, our findings show that high expression of MMP12 is correlated with the pathological stage and tumor metastasis of LAC patients, and knockdown of MMP12 suppresses the development of LAC cells, suggesting that MMP12 may be a promising therapeutic target for the treatment of LAC.

Knockdown of PTTG1 inhibits the growth and invasion of lung adenocarcinoma cells through regulation of TGFB1/SMAD3 signaling.

Increased expression of pituitary tumor-transforming gene 1 (PTTG1) is expressed in many tumors and regulates tumor growth and progression. However, the precise function of PTTG1 in the tumorigenesis of lung adenocarcinoma (LAC) is not defined yet. Here, we examined the expression of PTTG1 in human LAC tissues by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was carried out to investigate the effects of lentiviral vector-mediated PTTG1 shRNA (shPTTG1) on cell growth and invasive potential in LAC cell lines (A549 and LETPα-2), assessed by MTT and Transwell assays. As a consequence, we found that the expression of PTTG1 protein was markedly upregulated in LAC tissues compared with the adjacent non-cancerous tissues (ANCT) (54.0% vs. 28.0%, P = 0.008), and was positively associated with the lymphatic invasion of the tumor (P = 0.01). Moreover, knockdown of PTTG1 expression inhibited tumor proliferation and invasion of LAC cells, companied by the decreased expression of CyclinD1 and MMP-2 and increased expression of p-TGFβ1 and p-SMAD3. Collectively, our findings indicate that high expression of PTTG1 is correlated with the tumor metastasis of LAC patients, and knockdown of PTTG1 suppresses the growth and invasion of LAC cells through upregulation of the TGFβ1/SMAD3 signaling, suggesting that PTTG1 may be a potential target for developing an effective immunotherapeutic strategy for LAC.

17-AAG suppresses growth and invasion of lung adenocarcinoma cells via regulation of the LATS1/YAP pathway.

The large tumour suppressor 1 (LATS1) signalling network has been proved to be an essential regulator within the cell, participating in multiple cellular phenotypes. However, it is unclear concerning the clinical significance of LATS1 and the regulatory mechanisms of 17-Allylamino-17- demethoxygeldanamycin (17-AAG) in lung adenocarcinoma (LAC). The aim of the present study was to investigate the correlation of LATS1 and yes-associated protein (YAP) expression with clinicopathological characteristics in LAC patients, and the effects of 17-AAG on biological behaviours of LAC cells. Subcutaneous LAC tumour models were further established to observe the tumour growth in nude mice. The results showed that the positive expression of LATS1 was significantly lowered (26.7% versus 68.0%, P < 0.001), while that of YAP was elevated (76.0% versus 56.0%, P + 0.03) in LAC tissues compared to the adjacent non-cancerous tissues; LAST1 expression was negatively correlated with YAP expression (r + 0.432, P < 0.001) and lymphatic invasion of the tumour (P + 0.015). In addition, 17-AAG inhibited proliferation and invasion, and induced cell apoptosis and cycle arrest in LAC cells together with increased expression of E-cadherin and p-LATS1, and decreased expression of YAP and connective tissue growth factor. Tumour volumes and weight were much smaller in 17-AAG-treated groups than those in untreated group (P < 0.01). Taken together, our findings indicate that decreased expression of LATS1 is associated with lymphatic invasion of LAC, and 17-AAG suppresses growth and invasion of LAC cells via regulation of the LATS1/YAP pathway in vitro and in vivo, suggesting that we may provide a promising therapeutic strategy for the treatment of human LAC.

LAMC2 enhances the metastatic potential of lung adenocarcinoma.

Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin β1- and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target.

FOXM1 promotes lung adenocarcinoma invasion and metastasis by upregulating SNAIL.

The forkhead box M1 (FOXM1) transcription factor is one of the key genes inducing tumor invasion and metastasis by an unknown mechanism. In this study, we set out to investigate the effects of FOXM1 overexpression on metastatic human lung adenocarcinoma and the underlying mechanism. FOXM1 expression was analyzed in 78 frozen lung adenocarcinoma tissue samples using an Affymetrix microarray and a 155-paraffin-embedded lung adenocarcinoma tissue microarray with immunohistochemical detection. FOXM1 was found to be overexpressed in lung adenocarcinoma, particularly in metastatic patients, compared to non-metastatic patients. Knockdown of FOXM1 by a specific siRNA significantly suppressed EMT progression, migration and invasion of lung adenocarcinoma cells in vitro, and tumor growth and metastasis in vivo, whereas restored expression of FOXM1 had the opposite effect. FOXM1 binds directly to the SNAIL promoter through two specific binding sites and constitutively transactivates it. Collectively, our findings indicate that FOXM1 may play an important role in advancing lung adenocarcinoma progression. Aberrant FOXM1 expression directly and constitutively activates SNAIL, thereby promoting lung adenocarcinoma metastasis. Inhibition of FOXM1-SNAIL signaling may present an ideal target for future treatment.

MicroRNA-29a suppresses the growth, migration, and invasion of lung adenocarcinoma cells by targeting carcinoembryonic antigen-related cell adhesion molecule 6

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an important regulator of cell adhesion, invasion, and metastasis. The aim of this study was to evaluate the functional roles of CEACAM6 in lung adenocarcinoma and to identify miRNAs that inhibit the growth, migration, and invasion of lung adenocarcinoma cells by targeting CEACAM6. CEACAM6 expression is associated with poor prognosis of patients with lung adenocarcinoma, and CEACAM6 has important functional roles in controlling the growth, migration, and invasion of lung adenocarcinoma cells in vitro and in vivo. Furthermore, miR-29a can suppress the growth, migration, and invasion of lung adenocarcinoma cells by targeting CEACAM6. Therefore, miR-29a/CEACAM6 axis represents a potential therapeutic target for treatment of lung adenocarcinoma.

Benzo(a)pyrene promotes A549 cell migration and invasion through up-regulating Twist.

Benzo(a)pyrene (BaP) is one of the strongest carcinogens in cigarette smoke, which is an established human carcinogen. Twist, a transcription factor of the basic helix-loop-helix class, is reported to regulate lung cancer metastasis. Evidence has shown that BaP could induce Twist mRNA expression in non-small cell lung cancer (NSCLC) cell line A549 and promote lung adenocarcinoma cell invasion. However, it is unclear whether BaP promotes the migration and invasion of NSCLC cells by Twist modulation. A549 cell was exposed to BaP for different time. MTT assay was applied to assess cell proliferation. Silencing of Twist was done by small interfering RNA. Wound-healing assay was used to evaluate the capability of cell migration. Transwell assay was used to detect the capability of cell invasion. Western blotting and quantitative polymerase chain reaction were used to detect Twist expression. The levels of Twist protein expression and mRNA expression were increased with the treatment of BaP, compared with solvent control. The capability of wound healing of A549 cells was increased in BaP-treated group, compared with solvent control. BaP enhanced the capability of invasion of A549 cells. Twist knockdown could block the migration and invasion of A549 cells induced by BaP treatment. The mRNA levels of Twist were higher in metastatic NSCLC tissue samples than in primary NSCLC tissue samples, and higher levels of Twist mRNA were observed in metastatic NSCLC tissue samples with smoking history than in those with nonsmoking history. BaP treatment could promote the migration and invasion of NSCLC cells by up-regulating Twist expression.

The MZF1/c-MYC axis mediates lung adenocarcinoma progression caused by wild-type lkb1 loss.

Liver kinase B1 (LKB1) loss in lung adenocarcinoma is commonly caused by genetic mutations, but these mutations rarely occur in Asian patients. We recently reported wild-type LKB1 loss via the alteration of NKX2-1/p53-axis-promoted tumor aggressiveness and predicted poor outcomes in cases of lung adenocarcinoma. The mechanistic action of wild-type LKB1 loss within tumor progression remains unknown. The suppression of MYC by LKB1 controls epithelial organization; therefore, we hypothesize that MYC expression can be increased via wild-type LKB1 loss and promotes tumor progression. Here, MYC transcription is upregulated by LKB1-loss-mediated MZF1 expression. The wild-type LKB1-loss-mediated MZF1/MYC axis is responsible for soft-agar growth, migrationand invasion in lung adenocarcinoma cells. Moreover, wild-type LKB1 loss-induced cell invasiveness was markedly suppressed by MYC inhibitors (10058-F4 and JQ1). Patients with low-LKB1/high-MZF1 or low-LKB1/high-MYC tumors have shorter overall survival and relapse-free-survival periods than patients with high-LKB1/low-MZF1 or high-LKB1/low-MYCtumors. In summary, MZF1-mediated MYC expression may promote tumor progression, resulting in poor outcomes in cases of lung adenocarcinoma with low-wild-type-LKB1 tumors.