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Competing Interests: Declaration of Competing Interest The authors of the manuscript “Involvement of osteopontin, EpCAM, estrogen receptor-alpha, and carbonic anhydrase IX protein in managing lung cancer via Berberine loaded liquid crystalline nanoparticles”, submitted to the journal “Pathology - Research and Practice”, have no conflict of interest to declare.

Lung cancer (LC) is the leading cause of cancer-related deaths globally. It accounts for more than 1.9 million cases each year due to its complex and poorly understood molecular mechanisms that result in unregulated cell proliferation and metastasis. β-Catenin is a developmentally active protein that controls cell proliferation, metastasis, polarity and cell fate during homeostasis and aids in cancer progression via epithelial-mesenchymal transition. Therefore, inhibition of the β-catenin pathway could attenuate the progression of LC. Berberine, an isoquinoline alkaloid which is known for its anti-cancer and anti-inflammatory properties, demonstrates poor solubility and bioavailability. In our study, we have encapsulated berberine into liquid crystalline nanoparticles to improve its physiochemical functions and studied if these nanoparticles target the β-catenin pathway to inhibit the human lung adenocarcinoma cell line (A549) at both gene and protein levels. We observed for the first time that berberine liquid crystalline nanoparticles at 5 µM significantly attenuate the expression of the β-catenin gene and protein. The interaction between berberine and β-catenin was further validated by molecular simulation studies. Targeting β-catenin with berberine nanoparticles represents a promising strategy for the management of lung cancer progression., (© 2023. The Author(s).)

Lung cancer has the highest mortality rate compared to any other cancer worldwide, and cigarette smoking is one of the major etiological factors. How cigarette smoke (CS) induces tumorigenesis in healthy cells is still not completely understood. In this study, we treated healthy human bronchial epithelial cells (16HBE14o) with 1 % cigarette smoke extract (CSE) for one week. The CSE exposed cells showed upregulation of WNT/β-catenin pathway genes like WNT3, DLV3, AXIN and β-catenin, 30 oncology proteins were found to be upregulated after CSE treatment. Further, we explored whether the role of extracellular vesicles (EVs) obtained from CSE exposed cells can induce tumorigenesis. We observed that CSE EVs induced migration of healthy 16HBE14o cells by upregulation of various oncology proteins in recipient cells like AXL, EGFR, DKK1, ENG, FGF2, ICAM1, HMOX1, HIF1a, SERPINE1, SNAIL, HGFR, PLAU which are related to WNT signaling, epithelial mesenchymal transition (EMT) and Inflammation, whereas inflammatory marker, GAL-3 and EMT marker, VIM were downregulated. Moreover, β-catenin RNA was found in CSE EVs, upon treatment of these EVs to healthy cells, the β-catenin gene level was decreased in recipient cells compared to healthy 16HBE14o cells, indicating the utilisation of β-catenin RNA in healthy cells. Overall, our study suggests that CS treatment can induce tumorigenesis of healthy cells by upregulating WNT/β-catenin signaling in vitro and human lung cancer patients. Therefore targeting the WNT/β-catenin signaling pathway is involved in tumorigenesis inhibition of this pathway could be a potential therapeutic approach for cigarette smoke induced lung cancer., Competing Interests: Declaration of competing interest No competing interest to declare, (Copyright © 2023. Published by Elsevier Inc.)

Lung cancer is the leading cause of cancer-related deaths globally, in part due to a lack of early diagnostic tools and effective pharmacological interventions. Extracellular vesicles (EVs) are lipid-based membrane-bound particles released from all living cells in both physiological and pathological states. To understand the effects of lung-cancer-derived EVs on healthy cells, we isolated and characterized EVs derived from A549 lung adenocarcinoma cells and transferred them to healthy human bronchial epithelial cells (16HBe14o). We found that A549-derived EVs carry oncogenic proteins involved in the pathway of epithelial to mesenchymal transition (EMT) that are regulated by β-catenin. The exposure of 16HBe14o cells to A549-derived EVs resulted in a significant increase in cell proliferation, migration, and invasion via upregulating EMT markers such as E-Cadherin, Snail, and Vimentin and cell adhesion molecules such as CEACAM-5, ICAM-1, and VCAM-1, with concomitant downregulation of EpCAM. Our study suggests a role for cancer-cell-derived EVs to induce tumorigenesis in adjacent healthy cells by promoting EMT via β-catenin signaling.

Non-small cell lung cancer (NSCLC) is reported to have a high incidence rate and is one of the most prevalent types of cancer contributing towards 85% of all incidences of lung cancer. Berberine is an isoquinoline alkaloid which offers a broad range of therapeutical and pharmacological actions against cancer. However, extremely low water solubility and poor oral bioavailability have largely restricted its therapeutic applications. To overcome these limitations, we formulated berberine-loaded liquid crystalline nanoparticles (LCNs) and investigated their in vitro antiproliferative and antimigratory activity in human lung epithelial cancer cell line (A549). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), trypan blue staining, and colony forming assays were used to evaluate the anti-proliferative activity, while scratch wound healing assay and a modified Boyden chamber assay were carried out to determine the anti-migratory activity. We also investigated major proteins associated with lung cancer progression. The developed nanoparticles were found to have an average particle size of 181.3 nm with spherical shape, high entrapment efficiency (75.35%) and have shown sustained release behaviour. The most remarkable findings reported with berberine-loaded LCNs were significant suppression of proliferation, inhibition of colony formation, inhibition of invasion or migration via epithelial mesenchymal transition, and proliferation related proteins associated with cancer progression. Our findings suggest that anti-cancer compounds with the problem of poor solubility and bioavailability can be overcome by formulating them into nanotechnology-based delivery systems for better efficacy. Further in-depth investigations into anti-cancer mechanistic research will expand and strengthen the current findings of berberine-LCNs as a potential NSCLC treatment option., (© 2022. The Author(s).)