scholarly journals Targeting BMI1 and MCL1 for Lung Adenocarcinoma Treatment

2018 ◽  
Author(s):  
Erh-Hsuan Lin ◽  
Chiung-Fang Hsu ◽  
Yi-Hua Jan ◽  
Tsung-Hsien Lin ◽  
Hsiang-Yi Chang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Tumor Formation ◽  
Poor Survival ◽  
Cancer Stemness ◽  
Jnk Signaling ◽  
Chemotherapy Agent ◽  
Potential Strategy ◽  
Environment Stress ◽  
High Level

AbstractLung cancer is the leading cause of cancer-associated death worldwide. Early metastasis and the recurrence remain major challenges for lung cancer treatment in clinic. Targeting the cancer stemness could be a potential strategy to restrain tumor progression. In the current study, we found that in lung adenocarcinoma (LAC), BMI1 and MCL1 play crucial roles in invasion, chemo-resistance, and tumor initiation. JNK signaling is a link between oncogenic pathway or environment stress to cancer stemness. The activation of JNK, either by EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule BI-44 was synthesized, which effectively suppressed BMI1/MCL1 expression and inhibited tumor formation and progression in preclinical models. Targeting BMI1/MCL1 provides the basis for a new therapeutic approach in the treatment of LAC.

scholarly journals A clinical case of 3-year highly efficient pembrolizamable therapy of metasatic lung adenocarcinoma

2018 ◽  
pp. 9-10 ◽  
Author(s):  
K. K. Laktionov ◽  
D. I. Yudin ◽  
K. A. Sarantseva ◽  
K. P. Laktionov ◽  
V. V. Breder ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Clinical Case ◽  
Clinical Observation ◽  
Metastatic Adenocarcinoma ◽  
First Line ◽  
Highly Efficient ◽  
First Line Therapy ◽  
Line Therapy ◽  
High Level

Immunotherapy presents a new promising approach to the treatment of disseminated lung cancer. Pemriblisumab (Kitruda®) is one of the antiPD-1 drugs registered in Russia, which is used in both the secondand, in the event of high-level PD-L1 expression (≥50%), the first-line therapy. This paper presents a clinical observation of a highly efficient pemribrolizumab treatment of a patient with metastatic adenocarcinoma.

scholarly journals Generation of Stable cisPt Resistant Lung Adenocarcinoma Cells

2020 ◽  
Vol 13 (6) ◽  
pp. 109 ◽  
Author(s):  
Nico Ruprecht ◽  
Lukas Hofmann ◽  
Martin Nils Hungerbühler ◽  
Christoph Kempf ◽  
Johannes Thomas Heverhagen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Acquired Resistance ◽  
Advanced Lung Cancer ◽  
Anion Channels ◽  
Mechanisms Of Resistance ◽  
Adenocarcinoma Cells ◽  
A Cell ◽  
Lung Adenocarcinoma Cells ◽  
High Level

Platinum compounds represent the backbone of combined chemotherapy protocols for advanced lung cancer. The mechanisms responsible for its frequent primary or acquired resistance to cisplatin (cisPt)-based chemotherapy remains enigmatic. The availability of two cell lines of the same origin, one resistant and the other sensitive, will facilitate research to reveal the mechanism of resistance formation. Lung adenocarcinoma cells, A240286S (A24), were cultivated in increasing cisPt concentrations over a prolonged time. After a significant increase in IC50 was measured, cultivation of the cells was continued in absence of cisPt and IC50s determined over a long period (>7 months). As a result, a cell line with lasting, high-level cisPt resistance, designated (D-)A24cisPt8.0, was obtained. The cells were cross-resistant to oxaliplatin and to pemetrexed at a low level. Previous publications have claimed that Leucine-rich repeat-containing protein 8 (LRRC8A and LRRC8D) of the volume-regulated anion channels (VRACs) affect cellular resistance to cisPt. Even though cisPt decreased LRRC8D expression levels, we showed by knockdown and overexpression experiments with LRRC8A and D that these proteins do not govern the observed cisPt resistance. The tumor cell sublines described here provide a powerful model to study the mechanisms of resistance to cisPt in lung cancer cells and beyond.

High-level expression of Hsp90β is associated with poor survival in resectable non-small-cell lung cancer patients

2015 ◽  
Vol 67 (4) ◽  
pp. 509-519 ◽  
Author(s):  
Seok-Hyun Kim ◽  
Jun Ho Ji ◽  
Kyung Tae Park ◽  
Ji Hyun Lee ◽  
Kyung Woo Kang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Poor Survival ◽  
High Level Expression ◽  
Lung Cancer Patients ◽  
High Level

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.

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 Polycyclic Aromatic Hydrocarbon-induced Pulmonary Carcinogenesis in Cytochrome P450 (CYP)1A1- and 1A2-Null Mice: Roles of CYP1A1 and CYP1A2

2020 ◽  
Vol 177 (2) ◽  
pp. 347-361
Author(s):  
Grady Gastelum ◽  
Weiwu Jiang ◽  
Lihua Wang ◽  
Guodong Zhou ◽  
Roshan Borkar ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cytochrome P450 ◽  
Lung Adenocarcinoma ◽  
Tumor Formation ◽  
Human Lung Cancer ◽  
Wild Type ◽  
Polycyclic Aromatic ◽  
Pulmonary Carcinogenesis ◽  
The Individual

Abstract In 2019, lung cancer was estimated to be the leading cause of cancer deaths in humans. Polycyclic aromatic hydrocarbons (PAHs) are known to increase the risk of lung cancer. PAHs are metabolized by the cytochrome P450 (CYP)1A subfamily, comprised of the CYP1A1 and 1A2 monooxygenases. These enzymes bioactivate PAHs into reactive metabolites that induce mutagenic DNA adducts, which can lead to cancer. Past studies have investigated the role of CYP1A1 in PAH bioactivation; however, the individual roles of each CYP1A enzyme are still unknown. In this investigation, we tested the hypothesis that mice lacking the genes for Cyp1a1 or Cyp1a2 will display altered susceptibilities to PAH-induced pulmonary carcinogenesis. Wild-type, Cyp1a1-null (Cyp1a1−/−), and Cyp1a2-null (Cyp1a2−/−) male and female mice were treated with 3-methylcholanthrene for cancer initiation and tumor formation studies. In wild-type mice, CYP1A1 and 1A2 expression was induced by 3-methylcholanthrene. Cyp1a1−/− and Cyp1a2−/− mice treated with PAHs displayed a compensatory pattern, where knocking out 1 Cyp1a gene led to increased expression of the other. Cyp1a1−/− mice were resistant to DNA adduct and tumor formation, whereas Cyp1a2−/− mice displayed increased levels of both. UALCAN analysis revealed that lung adenocarcinoma patients with high levels of CYP1A2 expression survive significantly better than patients with low/medium expression. In conclusion, Cyp1a1−/− mice were less susceptible to PAH-induced pulmonary carcinogenesis, whereas Cyp1a2−/− mice were more susceptible. In addition, high CYP1A2 expression was found to be protective for lung adenocarcinoma patients. These results support the need to develop novel CYP1A1 inhibitors to mitigate human lung cancer.

scholarly journals Dissecting the multi-omics atlas of the exosomes released by human lung adenocarcinoma stem-like cells

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hai-Tao Luo ◽  
Yuan-Yuan Zheng ◽  
Jun Tang ◽  
Li-Juan Shao ◽  
Yi-Heng Mao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Regulatory Mechanisms ◽  
Cancer Development ◽  
Circular Rnas ◽  
Cell Populations ◽  
Poor Survival ◽  
Human Lung Adenocarcinoma ◽  
Tumor Exosomes

AbstractLung adenocarcinoma is heterogeneous and hierarchically organized, with a subpopulation of stem-like cells (CSCs) that reside at the apex of the hierarchy, in which exosomes act as important mediators by transporting specific molecules among different cell populations. Although there have been numerous studies on tumor exosomes, the constituents and functional properties of CSC-derived exosomes are still poorly characterized. Here we present a detail transcriptome and proteome atlas of the exosomes released by human lung adenocarcinoma stem-like cells (LSLCs). The transcriptome analysis indicates the specific patterns of exosomal constituents, including the fragmentation of transcripts and the low-level presence of circular RNAs, and identifies multiple exosomal-enriched mRNAs and lncRNAs. Integrative analysis of transcriptome and proteome data reveals the diverse functions of exosomal-enriched RNAs and proteins, many of which are associated with tumorigenesis. Importantly, several LSLC markers we identified are highly expressed in LSLC-derived exosomes and associate with poor survival, which may serve as promising liquid biopsy biomarkers for lung adenocarcinoma diagnosis. Our study provides a resource for the future elucidation of the functions of tumor-derived exosomes and their regulatory mechanisms in mediating lung cancer development.

CD26 is overexpressed in lung adenocarcinoma and qualifies as a therapeutic target against lung cancer

2018 ◽  
Author(s):  
N Enz ◽  
F Janker ◽  
F Ramírez Fragoso ◽  
M Haberecker ◽  
A Soltermann ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Therapeutic Target

Isoorientin Decreases Cell Migration via Decreasing Functional Activity and Molecular Expression of Proton-Linked Monocarboxylate Transporters in Human Lung Cancer Cells

2020 ◽  
Vol 48 (01) ◽  
pp. 201-222
Author(s):  
Hsu-Kai Huang ◽  
Shin-Yi Lee ◽  
Shu-Fen Huang ◽  
Yu-San Lin ◽  
Shih-Chi Chao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Lung Adenocarcinoma ◽  
Cell Viability ◽  
Cancer Cells ◽  
Functional Activity ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Human Lung Cancer Cells

Aggressive tumor cells mainly rely on glycolysis, and further release vast amounts of lactate and protons by monocarboxylate transporter (MCT), which causes a higher intracellular pH (pHi) and acidic extracellular pH. Isoorientin, a principle flavonoid compound extracted from several plant species, shows various pharmacological activities. However, effects of isoorientin on anticancer and MCT await to explore in human lung cancer cells. Human lung cancer tissues were obtained from cancer patients undergoing surgery, while the human lung adenocarcinoma cells (A549) were bought commercially. Change of pHi was detected by microspectrofluorometry method with a pH-sensitive fluorescent dye, BCECF. MTT and wound-healing assay were used to detect the cell viability and migration, respectively. Western blot techniques and immunocytochemistry staining were used to detect the protein expression. Our results indicated that the expression of MCTs1/4 and CD147 were upregulated significantly in human lung tissues. In experiments of A549 cells, under HEPES-buffer, the resting pHi was 7.47, and isoorientin (1–300[Formula: see text][Formula: see text]M) inhibited functional activity of MCT concentration-dependently (up to [Formula: see text]%). Pretreatment with isoorientin (3–100[Formula: see text][Formula: see text]M) for 24[Formula: see text]h, MCT activity and cell migration were significantly inhibited ([Formula: see text]% and [Formula: see text]%, respectively), while the cell viability was not affected. Moreover, the expression of MCTs1/4, CD147, and matrix metalloproteinase (MMP) 2/9 were significantly down regulated. In summary, MCTs1/4 and CD147 are significantly upregulated in human lung adenocarcinoma tissues, and isoorientin inhibits cells-migration by inhibiting activity/expression of MCTs1/4 and MMPs2/9 in human lung cancer cells. These novel findings suggest that isoorientin could be a promising pharmacological agent for lung cancer.

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