Increased α-actinin-1 destabilizes E-cadherin-based adhesions and associates with poor prognosis in basal-like breast cancer

Kovac, Bianca; Mäkelä, Tomi P.; Vallenius, Tea

doi:10.1371/journal.pone.0196986

Cited by 44 publications

(50 citation statements)

References 73 publications

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“…Additionally, membrane bound E-cadherin was lost indicating loss of cell-cell adhesion. To maintain a polarized epithelium, actin cytoskeleton co-operates with E-cadherin- and integrin-based cell-cell or cell-matrix adhesions[26]. α-actinin which is a major actin filament crosslinker was significantly upregulated in mild KC epithelium.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the mechanoresponsive role of β-catenin in Keratoconus epithelium

Amit

Padmanabhan

Janakiraman

2019

Preprint

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26 Keratoconus (KC) a disease with established biomechanical instability of the corneal stroma, is an 27 ideal platform to identify key proteins involved in mechanosensing. This study aims to investigate 28 the possible role of β-catenin as mechanotransducer in KC epithelium. KC patients were graded 29 as mild, moderate or severe using Amsler Krumeich classification. Immunoblotting and tissue 30 immunofluorescence studies were performed on KC epithelium to analyze the expression and 31 localization of β-catenin, E-cadherin, ZO1, α-catenin, Cyclin D1, α -actinin, RhoA, Rac123. Co-32 immunoprecipitation (Co-IP) of β-catenin followed by mass spectrometry of mild KC epithelium 33 was performed to identify its interacting partners. This was further validated by using epithelial 34 tissues grown on scaffolds of different stiffness. We observed down regulation of E-cadherin, α-35 catenin, ZO1 and upregulation of Cyclin D1, α -actinin and RhoA in KC corneal epithelium .β-36 catenin Co-IP from mild KC epithelium identified new interacting partners such as StAR-related 37 lipid transfer protein3 ,Dynamin-1-like protein, Cardiotrophin-1,Musculin, Basal cell adhesion 38 molecule and Protocadherin Fat 1.β-catenin localization was altered in KC which was validated in 39 vitro, using control corneal epithelium grown on different substrate stiffness. β-catenin localization 40 is dependent upon the elastic modulus of the substrate and acts as mechanotransducer by altering 41 its interaction and regulating the barrier function in corneal epithelium. 42 Keywords-β-catenin, Elastic modulus, Keratoconus, Mechanotransduction 43 Introduction 44 The mechanical properties of biological tissues are essential for their physiological functions[1]45 and their regulation plays an important role in driving various physiological and pathological 3 46 consequences [2]. Such regulation is based on mechanotransductional processes which initiate 47 distinct signalling pathways [3].The cell specific and molecular basis of mechanosensing and the 48 sequence of biochemical reactions that ensue, has been the focus of recent research [4]. Several 49 molecules have been proposed as possible mechanosensors such as integrins, ion channels, G-50 protein-coupled receptors, and cell-cell junctional proteins [5]. 51 Keratoconus (KC) is a bilateral progressive visually debilitating clinical condition characterized 52 by abnormal thinning and protrusion of the cornea in response to biomechanical instability of 53 the corneal stroma. The etiology of the disease is believed to be multifactorial with genetic and 54 environmental factors being implicated [6]. A decrease in the elastic modulus of the stromal 55 collagen is believed to initiate a cascade of events that results in morphological and biochemical 56 changes that affects the shape and the optical function of the cornea. Morphological changes in 57 the corneal epithelium have been well documented and are considered to be one of the earliest 58 detectable changes observed in KC [7]. Based on the hypothesis t...

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Section: Discussionmentioning

confidence: 99%

Deciphering the mechanoresponsive role of β-catenin in Keratoconus epithelium

Amit

Padmanabhan

Janakiraman

2019

Preprint

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“…Thirty out of 62 (48%) differentially expressed proteins between C1, C2, and C3 belonged to biological categories which characterized these TNBC clusters (Table ). These proteins were selected based on concordant ANOVA results between proteomics and transcriptomics data, and bibliographic analysis . Ten protein and RNA expression profiles were exactly the same between the three clusters (UGDH/ UGDH , K1C19/ KRT19 , FAS/ FASN , HYEP/ EPHX1 , BLVRB/ BLVRB , FSCN1/ FSCN1 , MOES/ MSN , FLNB/ FLNB , ACTN1/ ACTN1 , and SERPH/ SERPINH1 ).…”

Section: Resultsmentioning

confidence: 99%

“…These biological characteristics provide evidence of biological aggressiveness of C2 tumors compared to C1 and C3. Interferon pathway, represented by STAT1, SYWC, AMPL, TYPH, and SAMH1, [24] K2C8 (KRT8) [24] K1C18 (KRT18) [24] K1C19 (KRT19) [24] Androgen-regulated genes ANXA4 (ANXA4), [25] BLVRB (BLVRB) [25,26] FAS (FASN) [24][25][26][27] HYEP (EPHX1) [25] IDHC (IDH1) [25] UGDH (UGDH) [28] C2 Basal-like ILF2 (ILF2) [29] LDHB (LDHB) [30] Invasion, ECM ACTN1 (ACTN1) [31] FINC (FN1) [32][33][34] FLNB (FLNB) [35] FSCN1 (FSCN1) [36] PLOD3 (PLOD3) [33,37] POSTN (POSTN) [32][33][34] SERPH (SERPINH1) [33,38] TAGL2 (TAGLN2) [39] TENA (TNC) [32,33,40] TPIS (TPI1) [41] C3 Basal-like MOES (MSN) [42] Interferon pathway AMPL (LAP3) [43][44][45] SAMH1 (SAMHD1) [46] STAT1 (STAT1) [47] SYWC (WARS) [48] TYPH (TYMP) [49] Immunoglobulins IGHM (IGHM) [50] IGKC (IGKC) [50] and immunoglobulins, represented by IGKC and IGHM, support ...…”

Section: One-way Anovamentioning

confidence: 99%

iTRAQ‐Based Quantitative Proteomic Analysis Strengthens Transcriptomic Subtyping of Triple‐Negative Breast Cancer Tumors

et al. 2019

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Heterogeneity and lack of targeted therapies represent the two main impediments to precision treatment of triple‐negative breast cancer (TNBC). Therefore, molecular subtyping and identification of therapeutic pathways are required to optimize medical care. The aim of the present study is to define robust TNBC subtypes with clinical relevance by means of proteomics and transcriptomics. As a first step, unsupervised analyses are conducted in parallel on proteomics and transcriptomics data of 83 TNBC tumors. Proteomics data unsupervised analysis did not permit separation of TNBC into different subtypes, whereas transcriptomics data are able to clearly and robustly identify three subtypes: molecular apocrine (C1), basal‐like immune‐suppressed (C2), and basal‐like immune response (C3). Supervised analysis of proteomics data are then conducted based on transcriptomics subtyping. Thirty out of 62 proteins differentially expressed between C1, C2, and C3 belonged to biological categories which characterized these TNBC clusters: luminal and androgen‐regulated proteins (C1), basal, invasion, and extracellular matrix (C2), and basal and immune response (interferon pathway and immunoglobulins) (C3). Although proteomics unsupervised analysis of TNBC tumors is unsuccessful at identifying clusters, the integrated approach is promising. Identification and measurement of 30 proteins strengthen subtyping of TNBC based on robust transcriptomics unsupervised analysis.

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“…Also, we found that ACTN1 overexpression-induced HCC cell proliferation was largely abrogated by the inhibitors of the YAP-TEAD complex, indicating that ACTN1-induced HCC cell proliferation are dependent on the context of inhibition of Hippo signaling. Notably, ACTN1 is also involved in the focal adhesion kinase-Src complex formation [38], destabilization of E-cadherin-based adhesions [28], and luminogenesis [39]. Therefore, more works are needed to uncover whether these ACTN1-related activities are implicated in HCC development and progression.…”

Section: Discussionmentioning

confidence: 99%

ACTN1 Supports Tumor Growth by Inhibiting Hippo Signaling in Hepatocellular Carcinoma

Chen

Zhou

Zhang

et al. 2020

Preprint

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Background: Alpha actinins (ACTNs) are major cytoskeletal proteins and exhibit many non-muscle functions. Emerging evidence have uncovered the regulatory role of ACTNs in tumorigenesis, however, the expression pattern, biological functions, and underlying mechanism of ACTN1 in hepatocellular carcinoma (HCC) remain largely unexplored.Methods: Immunohistochemical analysis of a HCC tissue microarray (n = 157) was performed to determine the expression pattern and prognostic value of ACTN1 in HCC. In vitro loss-of-function study in HCC cells were carried out to investigate ACTN1 knockdown on cell proliferation. In vivo subcutaneous xenograft model and intrahepatic transplantation model were generated to decipher the contribution of ACTN1 in the tumor growth of HCC. Gene set enrichment analysis, quantitative real-time PCR, Co-immunoprecipitation, immunofluorescence and western blotting were performed to identify the underlying molecular mechanism.Results: It was found that ACTN1 was significantly upregulated in HCC tissues and closely related to llpha-fetoprotein level, tumor thrombus, tumor size, TNM stage and patient prognoses. Knockdown of ACTN1 suppressed in vitro cell proliferation and in vivo tumor growth of HCC cells. Mechanistically, knockdown of ACTN1 increased Hippo signaling pathway activity and decrease Rho GTPases activities. Mechanistically, ACTN1 could competitively interact with MOB1 and decrease the phosphorylation of LATS1 and YAP. The growth-promoting effect induced by ACTN1 was significantly abrogated by pharmacological inhibition of YAP with verteporfin or super-TDU.Conclusions: ACTN1 is highly expressed in HCC tissues and acts as a tumor promoter by suppressing Hippo signaling via physical interaction with MOB1. ACTN1 may serve as a potential prognostic marker and therapeutic target for HCC.

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Increased α-actinin-1 destabilizes E-cadherin-based adhesions and associates with poor prognosis in basal-like breast cancer

Cited by 44 publications

References 73 publications

Deciphering the mechanoresponsive role of β-catenin in Keratoconus epithelium

Deciphering the mechanoresponsive role of β-catenin in Keratoconus epithelium

iTRAQ‐Based Quantitative Proteomic Analysis Strengthens Transcriptomic Subtyping of Triple‐Negative Breast Cancer Tumors

ACTN1 Supports Tumor Growth by Inhibiting Hippo Signaling in Hepatocellular Carcinoma

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