The cell polarity protein Scrib functions as a tumor suppressor in liver cancer

Kapil, Shweta; Sharma, Bal Krishan; Patil, Mallikarjun; Elattar, Sawsan; Yuan, Jing; Hou, Steven X.; Kolhe, Ravindra; Satyanarayana, A.

doi:10.18632/oncotarget.15713

Cited by 30 publications

(29 citation statements)

References 56 publications

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“…Indeed, it was previously demonstrated that the loss of apical polarity primes S1 acini into cell cycle entry, but it is not sufficient to enhance proliferation [106]. In addition, depletion of Scrib in the breast, prostate, and liver accelerates tumor progression in the presence of other tumor-driving events but is not sufficient to drive tumorigenesis [104,107,108]. Blocking GJIC in 3-D cultures of S1 cells is not sufficient to enhance proliferation, although it acts in cooperation with extrinsic proliferation signals (Bazzoun/Adissu et al, submitted).…”

Section: Discussionmentioning

confidence: 99%

Connexin 43 Loss Triggers Cell Cycle Entry and Invasion in Non-Neoplastic Breast Epithelium: A Role for Noncanonical Wnt Signaling

Fostok

El‐Sibai

Bazzoun

et al. 2019

Cancers

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(1) Background: The expression of connexin 43 (Cx43) is disrupted in breast cancer, and re-expression of this protein in human breast cancer cell lines leads to decreased proliferation and invasiveness, suggesting a tumor suppressive role. This study aims to investigate the role of Cx43 in proliferation and invasion starting from non-neoplastic breast epithelium. (2) Methods: Nontumorigenic human mammary epithelial HMT-3522 S1 cells and Cx43 shRNA-transfected counterparts were cultured under 2-dimensional (2-D) and 3-D conditions. (3) Results: Silencing Cx43 induced mislocalization of β-catenin and Scrib from apicolateral membrane domains in glandular structures or acini formed in 3-D culture, suggesting the loss of apical polarity. Cell cycle entry and proliferation were enhanced, concomitantly with c-Myc and cyclin D1 upregulation, while no detectable activation of Wnt/β-catenin signaling was observed. Motility and invasion were also triggered and were associated with altered acinar morphology and activation of ERK1/2 and Rho GTPase signaling, which acts downstream of the noncanonical Wnt pathway. The invasion of Cx43-shRNA S1 cells was observed only under permissive stiffness of the extracellular matrix (ECM). (4) Conclusion: Our results suggest that Cx43 controls proliferation and invasion in the normal mammary epithelium in part by regulating noncanonical Wnt signaling.

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Section: Discussionmentioning

confidence: 99%

Connexin 43 Loss Triggers Cell Cycle Entry and Invasion in Non-Neoplastic Breast Epithelium: A Role for Noncanonical Wnt Signaling

Fostok

El‐Sibai

Bazzoun

et al. 2019

Cancers

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“…Our data also support the idea that disturbance of the three‐dimensional cellular organization can directly support tumor initiation—here in conjunction with the oncogene c‐MYC, which is frequently amplified in human HCCs—and that the cessation of hepatocellular polarity is not merely a consequence of malignant transformation. These findings of our study are supported by a very recent publication showing that Scrib is overexpressed and mislocalized in human HCC …”

Section: Discussionmentioning

confidence: 99%

“…Notably, our results showed strong positive effects of cytoplasmic Scrib on AKT signaling, but not on ERK1/2 or JNK signaling. Different effects were published for breast cancer and liver cells, where Scrib overexpression affected ERK1/2 activation and EMT . It is unclear whether these differences (regulation of AKT or ERK1/2) are due to cell type specific properties or if the differential localization of Scrib allows the regulation of both pathways under specific experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

et al. 2018

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“…SCRIB (Scrib) is an evolutionarily conserved component of a common genetic pathway involved in apical-basal cell polarity. Scrib inhibits liver cancer cell proliferation and functioning as a tumor suppressor in liver cancer [ 24 ]. SATB2 (special AT-rich sequence-binding protein 2), known as a nuclear matrix-associated transcription factor and epigenetic regulator, is an evolutionarily conserved transcription factor [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

A Five-Gene Signature for Recurrence Prediction of Hepatocellular Carcinoma Patients

Wang

et al. 2020

BioMed Research International

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Background. Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies with poor prognosis. There are many selectable treatments with good prognosis in Barcelona Clinic Liver Cancer- (BCLC-) 0, A, and B HCC patients, but the most crucial factor affecting survival is the high recurrence rate after treatments. Therefore, it is of great significance to predict the recurrence of BCLC-0, BCLC-A, and BCLC-B HCC patients. Aim. To develop a gene signature to enhance the prediction of recurrence among HCC patients. Materials and Methods. The RNA expression data and clinical data of HCC patients were obtained from the Gene Expression Omnibus (GEO) database. Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were conducted to screen primarily prognostic biomarkers in GSE14520. Multivariate Cox regression analysis was introduced to verify the prognostic role of these genes. Ultimately, 5 genes were demonstrated to be related with the recurrence of HCC patients and a gene signature was established. GSE76427 was adopted to further verify the accuracy of gene signature. Subsequently, a nomogram based on gene signature was performed to predict recurrence. Gene functional enrichment analysis was conducted to investigate the potential biological processes and pathways. Results. We identified a five-gene signature which performs a powerful predictive ability in HCC patients. In the training set of GSE14520, area under the curve (AUC) for the five-gene predictive signature of 1, 2, and 3 years were 0.813, 0.786, and 0.766. Then, the relative operating characteristic (ROC) curves of five-gene predictive signature were verified in the GSE14520 validation set, the whole GSE14520, and GSE76427, showed good performance. A nomogram comprising the five-gene signature was built so as to show a good accuracy for predicting recurrence-free survival of HCC patients. Conclusion. The novel five-gene signature showed potential feasibility of recurrence prediction for early-stage HCC.

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The cell polarity protein Scrib functions as a tumor suppressor in liver cancer

Cited by 30 publications

References 56 publications

Connexin 43 Loss Triggers Cell Cycle Entry and Invasion in Non-Neoplastic Breast Epithelium: A Role for Noncanonical Wnt Signaling

Connexin 43 Loss Triggers Cell Cycle Entry and Invasion in Non-Neoplastic Breast Epithelium: A Role for Noncanonical Wnt Signaling

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

A Five-Gene Signature for Recurrence Prediction of Hepatocellular Carcinoma Patients

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