LncRNA LINC00662 is closely related to the occurrence and development of cancer. This study aims to explore the effect of LINC00662 on colon cancer tumor growth and metastasis and its molecular mechanism. CCK8, colony formation, transwell, scratch wound, TUNEL, flow cytometry, RT-PCR, western blotting and immunohistochemistry assays were used to detect the proliferation, apoptosis, invasion and migration of colon cancer cell and mRNA and protein expressions. Luciferase reporter and RNA pull down assays were used to detect the combination of LINC00662 and miR-340-5p or IL22 and the combination of miR-340-5p and CLDN8/IL22. Co-immunoprecipitation were used to detect the co-expression of CLDN8 and IL22 in colon cell lines. The targets of LINC00662 were predicated by Starbase v2.0. The target genes of miR-340-5p were predicated by miRDB and TargetScan. GO and KEGG enrichment analysis were performed by DAVID website. LINC00662 was up-regulation in colon cancer tissues and cell lines. Univariate Cox regression analysis showed that the LINC00662 expression level was related to the poor prognosis. LINC00662-WT and miR-340-5p mimics co-transfection depressed luciferase activity and IL22/CLDN8-WT and miR-340-5p inhibitors co-transfection memorably motivated luciferase activity. LINC00662 overexpression promoted cell proliferation, invasion and migration, and inhibited cell apoptosis in colon cancer. In vivo xenograft studies in nude mice manifested that LINC00662 overexpression prominently accelerate tumor growth. There was an opposite reaction in the biological functions of colon cells and tumor growth between LINC00662 overexpression and LINC00662 inhibition in vitro and in vivo. The functions of miR-340-5p mimics regulating the biological functions of colon cells and tumor growth were consistent with those of LINC00662 inhibition. CLDN8 and IL22, as target genes of miR-340-5p, reversed the functions of LINC00662 affecting the biological functions of colon cells and the protein levels of Bax, Bcl-2, XIAP, VEGF, MMP-2, E-cadherin and N-cadherin. Co-immunoprecipitation experiments indicated that CLDN8 directly interact with IL22 in colon cell lines. LINC00662 regulated CLDN8 and IL22 expressions and the activation of ERK signaling pathway via targeting miR-340-5p. LINC00662 overexpression promoted the occurrence and development of colon cancer by competitively binding with miR-340-5p to regulate CLDN8/IL22 co-expression and activating ERK signaling pathway.

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LncRNA LINC00662 promotes colon cancer tumor growth and metastasis by competitively binding with miR-340-5p to regulate CLDN8/IL22 co-expression and activating ERK signaling pathway.

The mechanistic involvement of the renin-angiotensin system (RAS) reaches beyond cardiovascular physiopathology. Recent knowledge pinpoints a pleiotropic role for this system, particularly in the lung, and mainly through locally regulated alternative molecules and secondary pathways. Angiotensin peptides play a role in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. This manuscript reviews the literature supporting a role for the renin-angiotensin system in the lung tumor microenvironment and discusses whether blockade of this pathway in clinical settings may serve as an adjuvant therapy in lung cancer.

https://www.mdpi.com/2072-6694/12/6/1457/pdf

Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions.

Since its first description around the year 2000, the local renin-angiotensin system (RAS) in skin has been subject of an increasing number of studies with many additions over the last two to three years. A focus of research has been investigations on the role of cutaneous angiotensin receptors and locally synthesised angiotensin II in wound healing, in dermatoses associated with skin fibrosis and in melanoma. This review will provide an introduction into the RAS with emphasis on information relevant for the cutaneous RAS. It will discuss the role of the RAS in skin physiology, followed by a detailed review of the existing literature addressing the role of local angiotensin II and angiotensin AT1 and AT2 receptors in wound healing and in various skin diseases such as hypertrophic scars/keloids, scleroderma, dystrophic epidermolysis bullosa, Dupuytren's disease, squamous cell carcinoma, melanoma and psoriasis. In a final section, the potential relevance of drugs, which interfere with the RAS, for future therapy of dermatological disorders is discussed. Collectively, research about the RAS in skin can currently be described as an area, which has gained increasing attention by basic researchers, thus resulting in a multitude of preclinical studies pointing to the potential relevance of components of the RAS as drug targets in dermatological diseases. With a few small clinical studies already performed successfully for indications such as hypertrophic scars and keloids, it can be said that the skin RAS is now in the critical phase of translation from preclinical evidence to clinical use.

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The Role of the Renin-Angiotensin System in Skin Physiology and Pathophysiology.

The plasma membrane is a dynamic lipid bilayer that engages with the extracellular microenvironment and intracellular cytoskeleton. Caveolae are distinct plasma membrane invaginations lined by integral membrane proteins Caveolin1, 2, and 3. Caveolae formation and stability is further supported by additional proteins including Cavin1, EHD2, Pacsin2 and ROR1. The lipid composition of caveolar membranes, rich in cholesterol and phosphatidylserine, actively contributes to caveolae formation and function. Post-translational modifications of Cav1, including its phosphorylation of the tyrosine-14 residue (pY14Cav1) are vital to its function in and out of caveolae. Cells that experience significant mechanical stress are seen to have abundant caveolae. They play a vital role in regulating cellular signaling and endocytosis, which could further affect the abundance and distribution of caveolae at the PM, contributing to sensing and/or buffering mechanical stress. Changes in membrane tension in cells responding to multiple mechanical stimuli affects the organization and function of caveolae. These mechanical cues regulate pY14Cav1 levels and function in caveolae and focal adhesions. This review, along with looking at the mechanosensitive nature of caveolae, focuses on the role of pY14Cav1 in regulating cellular mechanotransduction.

Caveolin1 Tyrosine-14 Phosphorylation: Role in Cellular Responsiveness to Mechanical Cues

Protein tyrosine phosphorylation is one of the major post-translational modifications in eukaryotic cells and represents a critical regulatory mechanism of a wide variety of signaling pathways. Aberrant protein tyrosine phosphorylation has been linked to various diseases, including metabolic disorders and cancer. Few years ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors, able to block the signals emanated from receptor tyrosine kinases. However, recent evidence demonstrates that a misregulation of PTPs activity plays a critical role in cancer development and progression. Here, we will focus on PTP1B, an enzyme that has been linked to the development of type 2 diabetes and obesity through the regulation of insulin and leptin signaling, and with a promoting role in the development of different types of cancer through the activation of several pro-survival signaling pathways. In this review, we discuss the molecular aspects that support the crucial role of PTP1B in different cellular processes underlying diabetes, obesity and cancer progression, and its visualization as a promising therapeutic target.

Recent advances in PTP1B signaling in metabolism and cancer.

Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease.

https://www.mdpi.com/1422-0067/22/9/4823/pdf

Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development.

The renin-angiotensin receptor AT2R controls systemic blood pressure and is also suggested to modulate metastasis of cancer cells. However, in the latter case, the mechanisms involved downstream of AT2R remain to be defined. We recently described a novel Caveolin-1(CAV1)/Ras-related protein 5A (Rab5)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling axis that promotes metastasis in melanoma, colon, and breast cancer cells. Here, we evaluated whether the antimetastatic effect of AT2R is connected to inhibition of this pathway. We found that murine melanoma B16F10 cells expressed AT2R, while MDAMB-231 human breast cancer cells did not. AT2R activation blocked migration, transendothelial migration, and metastasis of B16F10(cav-1) cells, and this effect was lost when AT2R was silenced. Additionally, AT2R activation reduced transendothelial migration of A375 human melanoma cells expressing CAV1. The relevance of AT2R was further underscored by showing that overexpression of the AT2R in MDA-MB-231 cells decreased migration. Moreover, AT2R activation increased non-receptor protein tyrosine phosphatase 1B (PTP1B) activity, decreased phosphorylation of CAV1 on tyrosine-14 as well as Rab5/Rac1 activity, and reduced lung metastasis of B16F10(cav-1) cells in C57BL/6 mice. Thus, AT2R activation reduces migration, invasion, and metastasis of cancer cells by PTP1B-mediated CAV1 dephosphorylation and inhibition of the CAV1/Rab5/Rac-1 pathway. In doing so, these observations open up interesting, novel therapeutic opportunities to treat metastatic cancer disease.

https://www.mdpi.com/2072-6694/11/9/1299/pdf

AT2 Receptor Mediated Activation of the Tyrosine Phosphatase PTP1B Blocks Caveolin-1 Enhanced Migration, Invasion and Metastasis of Cancer Cells.

In recent decades, compelling evidence has emerged showing that organelles are not static structures but rather form a highly dynamic cellular network and exchange information through membrane contact sites. Although high-throughput techniques facilitate identification of novel contact sites (e.g., organelle-organelle and organelle-vesicle interactions), little is known about their impact on cellular physiology. Moreover, even less is known about how the dysregulation of these structures impacts on cellular function and therefore, disease. Particularly, cancer cells display altered signaling pathways involving several cell organelles; however, the relevance of interorganelle communication in oncogenesis and/or cancer progression remains largely unknown. This review will focus on organelle contacts relevant to cancer pathogenesis. We will highlight specific proteins and protein families residing in these organelle-interfaces that are known to be involved in cancer-related processes. First, we will review the relevance of endoplasmic reticulum (ER)-mitochondria interactions. This section will focus on mitochondria-associated membranes (MAMs) and particularly the tethering proteins at the ER-mitochondria interphase, as well as their role in cancer disease progression. Subsequently, the role of Ca2+ at the ER-mitochondria interphase in cancer disease progression will be discussed. Members of the Bcl-2 protein family, key regulators of cell death, also modulate Ca2+ transport pathways at the ER-mitochondria interphase. Furthermore, we will review the role of ER-mitochondria communication in the regulation of proteostasis, focusing on the ER stress sensor PERK (PRKR-like ER kinase), which exerts dual roles in cancer. Second, we will review the relevance of ER and mitochondria interactions with other organelles. This section will focus on peroxisome and lysosome organelle interactions and their impact on cancer disease progression. In this context, the peroxisome biogenesis factor (PEX) gene family has been linked to cancer. Moreover, the autophagy-lysosome system is emerging as a driving force in the progression of numerous human cancers. Thus, we will summarize our current understanding of the role of each of these organelles and their communication, highlighting how alterations in organelle interfaces participate in cancer development and progression. A better understanding of specific organelle communication sites and their relevant proteins may help to identify potential pharmacological targets for novel therapies in cancer control.

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Alejandra Sandoval-Bórquez

Papers

Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development.

AT2 Receptor Mediated Activation of the Tyrosine Phosphatase PTP1B Blocks Caveolin-1 Enhanced Migration, Invasion and Metastasis of Cancer Cells.

Perspectives on Organelle Interaction, Protein Dysregulation, and Cancer Disease