scholarly journals Hippo Pathway Deregulation Drives Tissue Stiffness and Cancer Stem-like Cells in Lung Adenocarcinoma

2018 ◽  
Author(s):  
Daniela Pankova ◽  
Yanyan Jiang ◽  
Iolanda Vendrell ◽  
Jon N. Buzzelli ◽  
Anderson Ryan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Extracellular Matrix ◽  
Lung Adenocarcinoma ◽  
Hippo Pathway ◽  
Metastatic Progression ◽  
Differentiation Markers ◽  
Cancer Stemness ◽  
Metastatic Dissemination

AbstractLung cancer remains the leading cause of cancer-related death due to poor treatment responses arising from tumor heterogeneity and epigenetic aberrations. Here we show that adverse prognosis associated with epigenetically silenced tumour suppressor RASSF1A is a consequence of increased extracellular matrix, tumour stiffness and metastatic dissemination in vivo and in vitro. We find that lung cancer cells with methylated RASSF1A display constitutive nuclear YAP1 and expression of prolyl4hydroxylase2 (P4HA2) into extracellular matrix that correlates with increases collagen deposition. Furthermore, we identify an epigenetic axis in tumour cells where elevated ECM impedes the intrinsic suppression of WNT signaling (via TPBG/5T4) triggering b-catenin-YAP1 activation and thus results in a cancer stem-like programming. As key drivers, we identified RASSF1A and P4HA2 mediating the ECM-dependent stemness and metastatic dissemination in vivo. Re-expression of RASSF1A or inhibition of P4HA2 activity reverse these effects and increase levels of lung differentiation markers (TTF-1, Mucin5B) in vivo and in vitro. Our study identifies an epigenetic program to cancer stemness and metastatic progression of lung adenocarcinoma and P4HA2 as potential target for uncoupling ECM signals towards cancer stemness.

scholarly journals ALCAP2 inhibits lung adenocarcinoma cell proliferation, migration and invasion via the ubiquitination of β-catenin by upregulating the E3 ligase NEDD4L

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Weijie Zhang ◽  
Ruochen Zhang ◽  
Yuanyuan Zeng ◽  
Yue Li ◽  
Yikun Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Nuclear Translocation ◽  
E3 Ligase ◽  
Migration And Invasion ◽  
Drug Candidate ◽  
Proliferation And Metastasis

AbstractLung cancer is recognized as the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype, accounting for approximately 85% of lung cancer cases. Although great efforts have been made to treat lung cancer, no proven method has been found thus far. Considering β, β-dimethyl-acryl-alkannin (ALCAP2), a natural small-molecule compound isolated from the root of Lithospermum erythrorhizon. We found that lung adenocarcinoma (LUAD) cell proliferation and metastasis can be significantly inhibited after treatment with ALCAP2 in vitro, as it can induce cell apoptosis and arrest the cell cycle. ALCAP2 also significantly suppressed the volume of tumours in mice without inducing obvious toxicity in vivo. Mechanistically, we revealed that ALCAP2-treated cells can suppress the nuclear translocation of β-catenin by upregulating the E3 ligase NEDD4L, facilitating the binding of ubiquitin to β-catenin and eventually affecting the wnt-triggered transcription of genes such as survivin, cyclin D1, and MMP9. As a result, our findings suggest that targeting the oncogene β-catenin with ALCAP2 can inhibit the proliferation and metastasis of LUAD cells, and therefore, ALCAP2 may be a new drug candidate for use in LUAD therapeutics.

scholarly journals The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Long Gao ◽  
Yuan Liu ◽  
Xiaohong Du ◽  
Sai Ma ◽  
Minmin Ge ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Enzymatic Activity ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
In Vitro Assays ◽  
Knock Out

AbstractIt has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.

ZNF280A Promotes Lung Adenocarcinoma Development through Regulating the Expression of EIF3C

2020 ◽  
Author(s):  
Hongsheng Liu ◽  
Yingzhi Qin ◽  
Na Zhou ◽  
Dongjie Ma ◽  
Yingyi Wang
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Small Cell Lung ◽  
Normal Tissues ◽  
Tumor Promotor ◽  
And Migration ◽  
First Time ◽  
The Relationship

Abstract Background: Lung cancer is the most commonly diagnosed malignant tumor worldwide. Lung adenocarcinoma (LUAD) is the most common histological subtype in non-small cell lung cancer (NSCLC). The relationship between ZNF280A and LUAD has not been demonstrated and remains unclear. Methods: In this study, it was demonstrated that ZNF280A was upregulated in LUAD tissues compared with the normal tissues. Further investigations indicated that the overexpression/knockdown of ZNF280A could promote/inhibit proliferation, colony formation and migration of LUAD cells, while inhibiting/promoting cell apoptosis. Moreover, knockdown of ZNF280A could also suppress tumorigenicity of LUAD cells in vivo. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed for exploring downstream of ZNF280A and identified EIF3C as the potential target. Results: Furthermore, our study revealed that knockdown of EIF3C could inhibit development of LUAD in vitro, and alleviate the ZNF280A overexpression induced promotion of LUAD. Conclusions: In conclusion, our study showed, as the first time, ZNF280A as a tumor promotor for LUAD, whose function was carried out probably through the regulation of EIF3C.

HOXA4-Dependent Transcriptional Activation of AXL Promotes Cisplatin- Resistance in Lung Adenocarcinoma Cells

2019 ◽  
Vol 18 (14) ◽  
pp. 2062-2067 ◽  
Author(s):  
Shuo Yu ◽  
Hui Ren ◽  
Yang Li ◽  
Xuan Liang ◽  
Qian Ning ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcriptional Regulation ◽  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Cisplatin Resistance ◽  
Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells ◽  
Encoding Gene

Background: Lung cancer is one of the most leading causes of cancer-related deaths in adults worldwide. Non-Small Cell Lung Cancer (NSCLC), which comprises 80 to 85% of all lung cancers, is the most lethal subtype of lung cancer with a 5-year survival of less than 13%. In this study, we identified a poorly-studied kinase PDK4 as the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma. Methods: In vitro cell viability assay and in vivo tumor xenograft assay were used in the detection of cell proliferation. RNA isolation, quantitative Real-Time PCR, Western blot analysis, immunohistochemistry were used to investigate the expression of RNA and protein. Lentivirus infection was used to regulate gene expression. Luciferase assays were used to monitor EPAS1 promoter activity. Results: In vivo PDK4 expression was elevated in a Cisplatin-resistant population of lung adenocarcinoma cells, PDK4-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma in vivo and in vitro, clinically PDK4 expression was associated with poor prognosis in lung adenocarcinoma patients, mechanically PDK4 promoted cell growth and Cisplatin-resistance of lung adenocarcinoma via transcriptional regulation of endothelial PAS domain-containing protein 1 (EPAS1). Conclusion: PDK4 is the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma and PDK4-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma mainly through transcriptional regulation of EPAS1. Enriched PDK4 expression was correlated with the poor prognosis of lung cancer patients, indicating that PDK4 could be a potential therapeutic target for Cisplatin-resistant lung adenocarcinoma.

scholarly journals Lung adenocarcinoma cell-derived exosomal miR-328 promote osteoclastogenesis by targeting Nrp2

2021 ◽  
Author(s):  
Cheng Cheng Zhang ◽  
Jingru Qin ◽  
Lu Yang ◽  
Zhiyao Zhu ◽  
Xinle Qian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Bone Resorption ◽  
Lung Adenocarcinoma ◽  
Adenocarcinoma Cell ◽  
Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells

Bone metastasis of lung cancer and detailed mechanisms are still elusive, and the roles of exosomes derived from lung adenocarcinoma cells in this process have attracted much attention. In this study, we found that lung adenocarcinoma cell-derived exosomes (LCC-Exos) promoted osteogenesis and bone resorption in vitro. Furthermore, LCC-Exos target bone in vivo and promoted bone resorption in vivo. Mechanistically, LCC-Exosomal miR-328 promoted bone resorption by targeting Nrp2 and LCC-ExosmiR-328 Inhibitors inhibited bone resorption in vivo. Thus, LCC-Exosomal miR-328 promote osteoclastogenesis by targeting Nrp2 and LCC-ExosmiR-328 Inhibitors may serve as a potential nanomedicine for the treatment of bone metastasis.

scholarly journals C1GALT1, Negatively Regulated by miR-181d-5p, Promotes Tumor Progression via Upregulating RAC1 in Lung Adenocarcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaoxia Dong ◽  
Yongyu Liu ◽  
Xinzhou Deng ◽  
Jun Shao ◽  
Shuangyue Tian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Bioinformatic Analysis ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Migration And Invasion ◽  
Loss Of Function

Glycosyltransferases are frequently dysregulated in lung cancer. Core 1 β 1, 3-galactosyltransferase 1 (C1GALT1), an enzyme highly expressed in various cancers, is correlated with tumor initiation and development. However, the role of C1GALT1 in lung cancer remains poorly understood. In this study, through bioinformatic analysis and clinical validation, we first discovered that C1GALT1 expression was upregulated in lung adenocarcinoma (LUAD) tissues and was closely related to poor prognosis in patients with LUAD. Gain- and loss-of-function experiments showed that C1GALT1 promoted LUAD cell proliferation, migration, and invasion in vitro, as well as tumor formation in vivo. Further investigation demonstrated that RAC1 expression was positively regulated by C1GALT1 in LUAD, whereas silencing Rac1 could reverse C1GALT1-induced tumor growth and metastasis. Moreover, miR-181d-5p was identified as a negative regulator for C1GALT1 in LUAD. As expected, the inhibitory effects of miR-181d-5p on LUAD cell proliferation, migration, and invasion were counteracted by restoration of C1GALT1. In summary, our results highlight the importance of the miR-181d-5p/C1GALT1/RAC1 regulatory axis during LUAD progression. Thus, C1GALT1 may serve as a potential therapeutic target for LUAD.

STK33-dependent transcriptional regulation of SFTA3 induces Cisplatin-resistance in lung adenocarcinoma

2019 ◽  
Vol 19 ◽  
Author(s):  
Kuilong Zhou ◽  
Runzhi Dong ◽  
Zhiheng Wang ◽  
Zhian Tang ◽  
Xuezhen Gao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcriptional Regulation ◽  
Lung Adenocarcinoma ◽  
Cisplatin Resistance ◽  
Serine Threonine Kinase ◽  
Lung Cancer Patients ◽  
Threonine Kinase ◽  
Signaling Axis

: Drug-resistance has become a major obstacle for Cisplatin usage in non-small cell lung cancer. In this study, we identified a poorly-studied kinase Serine/Threonine Kinase 33 (STK33) as the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma. Additionally, STK33-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma both in vitro and in vivo. Clinically, STK33 expression was enriched in lung adenocarcinoma and was correlated to poor prognosis of lung cancer patients. Mechanically, STK33 promoted cell growth and Cisplatin-resistance of lung adenocarcinoma via transcriptional regulation of surfactant associated 3 (SFTA3), indicating that STK33-SFTA3 signaling axis could be a potential therapeutic target for Cisplatin-resistant lung adenocarcinoma.

scholarly journals Upregulated Collagen COL10A1 Remodels the Extracellular Matrix and Promotes Malignant Progression in Lung Adenocarcinoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Yingkuan Liang ◽  
Wenjie Xia ◽  
Te Zhang ◽  
Bing Chen ◽  
Hui Wang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Expression Profiles ◽  
Ectopic Expression ◽  
Loss Of Function ◽  
Mechanism Study ◽  
Cell Progression

Collagens are major components of the ECM in various organs, including the lungs. Ectopic expression of collagens can regulate the tumor progression and disease outcome through remodeling of the extracellular matrix (ECM). However, it remains largely unexplored whether collagens are involved in the tumor progression of lung adenocarcinoma (LUAD). Analysis of three LUAD transcriptional expression profiles showed that COL10A1 mRNA expression was up-regulated and associated with poor prognosis. Gain- and loss-of-function studies were performed to observe that up-regulated COL10A1 promotes LUAD cell proliferation and invasion in vitro and in vivo. In molecular mechanism study, we found that COL10A1 interacts with DDR2 and affects the downstream FAK signaling pathway to regulate LUAD cell progression. The expression of COL10A1 on tissue microarray (TMA) was also measured to explore the association between COL10A1 expression and patient outcome. The results addressed that COL10A1 is up-regulated and positively correlated with lymph node metastasis in lung adenocarcinoma, and the COL10A1 expression is also an independent prognostic factor. In summary, the up-regulated COL10A1 remodels the ECM and the COL10A1/DDR2/FAK axis regulates the proliferation and metastasis of LUAD cells, implying that COL10A1 is a promising therapeutic target and prognostic marker for LUAD patients.

scholarly journals MicroRNA-106a regulates autophagy-related cell death and EMT by targeting TP53INP1 in lung cancer with bone metastasis

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Lei Han ◽  
Zeyong Huang ◽  
Yan Liu ◽  
Lijuan Ye ◽  
Dongqi Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Lung Adenocarcinoma ◽  
Cancer Patients ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Lung Cancer Patients

AbstractBone metastasis is one of the most serious complications in lung cancer patients. MicroRNAs (miRNAs) play important roles in tumour development, progression and metastasis. A previous study showed that miR-106a is highly expressed in the tissues of lung adenocarcinoma with bone metastasis, but its mechanism remains unclear. In this study, we showed that miR-106a expression is dramatically increased in lung cancer patients with bone metastasis (BM) by immunohistochemical analysis. MiR-106a promoted A549 and SPC-A1 cell proliferation, migration and invasion in vitro. The results of bioluminescence imaging (BLI), micro-CT and X-ray demonstrated that miR-106a promoted bone metastasis of lung adenocarcinoma in vivo. Mechanistic investigations revealed that miR-106a upregulation promoted metastasis by targeting tumour protein 53-induced nuclear protein 1 (TP53INP1)-mediated metastatic progression, including cell migration, autophagy-dependent death and epithelial–mesenchymal transition (EMT). Notably, autophagy partially attenuated the effects of miR-106a on promoting bone metastasis in lung adenocarcinoma. These findings demonstrated that restoring the expression of TP53INP1 by silencing miR-106a may be a novel therapeutic strategy for bone metastatic in lung adenocarcinoma.

scholarly journals Tobacco carcinogen-induced mouse lung adenocarcinoma cell lines as tools to identify novel lung cancer genes

2018 ◽  
Author(s):  
Νικόλαος Κανελλάκης
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cell Lines ◽  
Mouse Lung ◽  
Cancer Genes ◽  
Adenocarcinoma Cell ◽  
Tobacco Carcinogen

Η νόσος του καρκίνου αποτελεί ένα σημαντικό και βαρύ κοινωνικό-οικονομικό φορτίο τόσο για τις οικονομικά αναπτυγμένες όσο και για τις οικονομικά αναπτυσσόμενες κοινωνίες. Η συχνότητα της διάγνωσης καρκινικών περιστατικών δείχνει να αυξάνεται με την πάροδο του χρόνου λόγω της γήρανσης του πληθυσμού και της αδυναμίας περιορισμού της χρήσης παραγόντων οι οποίοι έχουν συσχετιστεί με τον κίνδυνο εμφάνισης καρκίνου, όπως το κάπνισμα. Ο καρκίνος του πνεύμονα αποτελεί την κύρια αιτία θανάτου από καρκίνο παγκοσμίως. Οι κακοήθειες οι οποίες επάγονται από καρκινογόνα, συμπεριλαμβανομένου του πνευμονικού αδενοκαρκινώματος των καπνιστών, περιέχουν χιλιάδες μεταλλάξεις στο γονιδίωμά τους. Τις τελευταίες δεκαετίες έχουν ανακαλυφθεί και μελετηθεί πολλά νέα ογκογονίδια συσχετιζόμενα με το αδενοκαρκίνωμα πνεύμονα με αποτέλεσμα να εισαχθούν στην κλινική πράξη νέοι αντικαρκινικοί παράγοντες οι οποίοι άλλαξαν την πρόγνωση των ασθενών και βελτίωσαν την ποιότητα της ζωής τους. Ωστόσο, λόγω περιορισμών σχεδόν στα μισά περιστατικά τα ογκογονίδια τα οποία ευθύνονται για την ανάπτυξη των νεοπλασμάτων δεν είναι δυνατό να εντοπιστούν και έτσι παραμένουν άγνωστα. Παρά την ύπαρξη περίτεχνων γενετικών μοντέλων ποντικών του καρκίνου του πνεύμονα, αδυνατούν να προσομοιώσουν την ανθρώπινη νόσο με ακρίβεια και πιστότητα. Η ανάπτυξη ενός αξιόπιστου μοντέλου ποντικών το οποίο θα μπορούσε να χρησιμοποιηθεί για την εντοπισμό των ογκογονιδίων και μεταλλάξεων του καρκίνου πνεύμονα παραμένει μια μη ικανοποιημένη και ιδιαίτερα σημαντική ερευνητική ανάγκη. Καταφέραμε να αναπτύξουμε μια μεθοδολογία για τη δημιουργία κυτταρικών σειρών αδενοκαρκινώματος πνεύμονα ποντικού από διάφορα στελέχη μετά από επαναλαμβανόμενη έκθεση στις καρκινογόνες ουσίες του καπνού: ουρεθάνη και διαιθυλο νιτροζαμίνη. Οι κυτταρικές σειρές οι οποίες προέκυψαν (n = 7) ήταν αθάνατες και φαινοτυπικά σταθερές in vitro, ογκογόνες, μεταστατικές και θανατηφόρες in vivo. Οι επαγόμενες από χημικά καρκινογόνα του καπνού κυτταρικές σειρές παρουσίασαν αξιοσημείωτη ομοιότητα με το ανθρώπινο αδενοκαρκίνωμα πνεύμονα, καθώς περιείχαν μεταλλάξεις στα γονίδια Kras και Trp53 και παρουσίασαν χαρακτηριστικές ιδιότητες των καρκινικών βλαστοκυττάρων. Ανακαλύψαμε ότι όλες οι κυτταρικές σειρές υπερέκφραζαν το γονίδιο Proliferin, ένα ορθολογo στον ποντικό για την ανθρώπινη προλακτίνη. Η λειτουργική μελέτη του γονιδίου έδειξε πως δρα ως υποκινητής για την αναπτυξη πνευμονικών όγκων. Είναι ενδιαφέρον το γεγονός πως η προλακτίνη βρέθηκε υπερεκφρασμένη και συσχετίστηκε με κακή πρόγνωση στο ανθρώπινο αδενοκαρκίνωμα πνεύμονα. Συμπερασματικά τα κύτταρα αδενοκαρκινώματος πνεύμονα ποντικού τα οποία δημιουργήσαμε με τη χρήση καρκινογόνων του καπνού μοιάζουν με την ανθρώπινη νόσο του αδενοκαρκινώματος πνεύμονα. Ως εκ τούτου μπορούν να χρησιμοποιηθούν ως ένα πολύτιμο εργαλείο για την ανακάλυψη και τη λειτουργική διερεύνηση νέων ογκογονιδίων του αδενοκαρκινώματος του πνεύμονα, των μεταλλάξεων που οδηγούν στην ανάπτυξή του και των βιολογικών μονοπατιών και μηχανισμών που προάγουν την πνευμονική καρκινογένεση.ΛΕΞΕΙΣ ΚΛΕΙΔΙΑπνεύμονας; αδενοκαρκίνωμα; καπνός; καρκινογόνο; κάπνισμα; KRAS; TRP53

Sign in / Sign up

Export Citation Format

Share Document