|
1
|
Ji HS. Research and analysis of circulating tumor cell detection in the diagnosis and treatment of gastric cancer. World J Gastrointest Oncol 2025; 17:102329. [PMID: 40092958 PMCID: PMC11866229 DOI: 10.4251/wjgo.v17.i3.102329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/27/2024] [Accepted: 12/30/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs) are crucial for improving our knowledge regarding tumor progress, prognosis, and recurrence possibility. AIM To evaluate the role of CTCs in the early diagnosis and treatment of gastric cancer. METHODS From June 2020 to December 2021, a randomized study was conducted in our institution involving 80 patients scheduled for surgery for gastric cancer. The patients were divided into two groups: A control group that was tested for traditional serum markers and a study group that was assessed for serum CTCs. RESULTS In the study cohort, CTC levels did not correlate significantly with patient age, gender, or degree of tumor differentiation (P > 0.05). However, there was a significant correlation with the tumor-node-metastasis stage of the tumor (P < 0.05). In the study group, the CTC diagnostic positivity rate was 62.50% (25 out of 40 patients), while the positivity rate for conventional serum markers in the control group was 47.50% (19 out of 40 patients). The positive detection rate in the study group was significantly higher than that of the control group (P < 0.05). CONCLUSION CTCs have slight invasion and high sensitivity and specificity, presenting great value for early clinical diagnosis of recurrence and metastasis. It will improve the deceleration of disease development and increase the survival rate.
Collapse
Affiliation(s)
- Han-Shu Ji
- Second Department of General Surgery, Cangzhou Central Hospital, Cangzhou 061000, Hebei Province, China
| |
Collapse
|
|
2
|
Zhang Y, Chen J, Tian J, Zhou Y, Liu Y. Role and function of plakophilin 3 in cancer progression and skin disease. Cancer Sci 2024; 115:17-23. [PMID: 38048779 PMCID: PMC10823275 DOI: 10.1111/cas.16019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 10/30/2023] [Accepted: 11/06/2023] [Indexed: 12/06/2023] Open
Abstract
Plakophilin 3 (PKP3), a component of desmosome, is aberrantly expressed in many kinds of human diseases, especially in cancers. Through direct interaction, PKP3 binds with a series of desmosomal proteins, such as desmoglein, desmocollin, plakoglobin, and desmoplakin, to initiate desmosome aggregation, then promotes its stability. As PKP3 is mostly expressed in the skin, loss of PKP3 promotes the development of several skin diseases, such as paraneoplastic pemphigus, pemphigus vulgaris, and hypertrophic scar. Moreover, accumulated clinical data indicate that PKP3 dysregulates in diverse cancers, including breast, ovarian, colon, and lung cancers. Numerous lines of evidence have shown that PKP3 plays important roles in multiple cellular processes during cancer progression, including metastasis, invasion, tumor formation, autophagy, and proliferation. This review examines the diverse functions of PKP3 in regulating tumor formation and development in various types of cancers and summarizes its detailed mechanisms in the occurrence of skin diseases.
Collapse
Affiliation(s)
- Yefei Zhang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Institute of Cancer, Department of Biochemistry, College of Life ScienceNanjing Normal UniversityNanjingChina
| | - Jiahui Chen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Institute of Cancer, Department of Biochemistry, College of Life ScienceNanjing Normal UniversityNanjingChina
| | - Jia Tian
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Institute of Cancer, Department of Biochemistry, College of Life ScienceNanjing Normal UniversityNanjingChina
| | - Yehui Zhou
- Department of General SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Yan Liu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Institute of Cancer, Department of Biochemistry, College of Life ScienceNanjing Normal UniversityNanjingChina
| |
Collapse
|
|
3
|
Du Y, Hou S, Chen Z, Li W, Li X, Zhou W. Comprehensive Analysis Identifies PKP3 Overexpression in Pancreatic Cancer Related to Unfavorable Prognosis. Biomedicines 2023; 11:2472. [PMID: 37760912 PMCID: PMC10526039 DOI: 10.3390/biomedicines11092472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 09/04/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Plakophilin 3 (PKP3) affects cell signal transduction and cell adhesion and performs a crucial function in tumorigenesis. The current investigation evaluated the predictive significance and underlying processes of PKP3 within pancreatic cancer (PC) tissues. The assessment of differences in PKP3 expression was conducted through an analysis of RNA-seq data acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Additionally, clinical samples were collected to validate the findings. The predictive significance of PKP3 was investigated by analyzing survival data derived from TCGA and clinical specimens. PKP3's biological function was assessed via phenotypic experiments after the suppression of PKP3 expression within PC cells. Functional enrichment analysis, encompassing KEGG, GO, and GSEA, was employed to assess the underlying mechanism of PKP3. Immune infiltration analysis was conducted in the present investigation to determine the association between PKP3 and tumor-infiltrating immune cells (TICs). In PC tissues, PKP3 expression was abnormally upregulated and correlated with a negative prognosis in individuals with PC. PKP3 can promote the progression, migration, and invasive capacity of PC cells and is relevant to the regulation of the PI3K-Akt and MAPK signaling pathways. Immune infiltration analysis demonstrated that PKP3 impeded CD8+ T-cell infiltration and immune cytokine expression within the tumor microenvironment. The PKP3 protein was identified as a prospective independent predictive indicator and represents a viable approach for immunotherapy in the context of PC. PKP3 may impact prognosis by broadly inhibiting immune cell infiltration and promoting the activation of tumor-associated signaling pathways.
Collapse
Affiliation(s)
- Yan Du
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China
| | - Shuang Hou
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China
| | - Zhou Chen
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730030, China
| | - Wancheng Li
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China
| | - Xin Li
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Wence Zhou
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China
| |
Collapse
|
|
4
|
Müller L, Keil R, Hatzfeld M. Plakophilin 3 facilitates G1/S phase transition and enhances proliferation by capturing RB protein in the cytoplasm and promoting EGFR signaling. Cell Rep 2023; 42:112031. [PMID: 36689330 DOI: 10.1016/j.celrep.2023.112031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 10/26/2022] [Accepted: 01/10/2023] [Indexed: 01/23/2023] Open
Abstract
Plakophilin 3 (PKP3) is a component of desmosomes and is frequently overexpressed in cancer. Using keratinocytes either lacking or overexpressing PKP3, we identify a signaling axis from ERK to the retinoblastoma (RB) protein and the E2F1 transcription factor that is controlled by PKP3. RB and E2F1 are key components controlling G1/S transition in the cell cycle. We show that PKP3 stimulates the activity of ERK and its target RSK1. This inhibits expression of the transcription factor RUNX3, a positive regulator of the CDK inhibitor CDKN1A/p21, which is also downregulated by PKP3. Elevated CDKN1A prevents RB phosphorylation and E2F1 target gene expression, leading to delayed S phase entry and reduced proliferation in PKP3-depleted cells. Elevated PKP3 expression not only increases ERK activity but also captures phosphorylated RB (phospho-RB) in the cytoplasm to promote E2F1 activity and cell-cycle progression. These data identify a mechanism by which PKP3 promotes proliferation and acts as an oncogene.
Collapse
Affiliation(s)
- Lisa Müller
- Charles Tanford Protein Research Center, Martin Luther University Halle, Institute of Molecular Medicine, Department for Pathobiochemistry, Kurt-Mothes-Str. 3A, 06120 Halle, Germany.
| | - René Keil
- Charles Tanford Protein Research Center, Martin Luther University Halle, Institute of Molecular Medicine, Department for Pathobiochemistry, Kurt-Mothes-Str. 3A, 06120 Halle, Germany
| | - Mechthild Hatzfeld
- Charles Tanford Protein Research Center, Martin Luther University Halle, Institute of Molecular Medicine, Department for Pathobiochemistry, Kurt-Mothes-Str. 3A, 06120 Halle, Germany.
| |
Collapse
|
|
5
|
Schamschula E, Lahnsteiner A, Assenov Y, Hagmann W, Zaborsky N, Wiederstein M, Strobl A, Stanke F, Muley T, Plass C, Tümmler B, Risch A. Disease-related blood-based differential methylation in cystic fibrosis and its representation in lung cancer revealed a regulatory locus in PKP3 in lung epithelial cells. Epigenetics 2021; 17:837-860. [PMID: 34415821 PMCID: PMC9423854 DOI: 10.1080/15592294.2021.1959976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Cystic fibrosis (CF) is a monogenic disease, characterized by massive chronic lung inflammation. The observed variability in clinical phenotypes in monozygotic CF twins is likely associated with the extent of inflammation. This study sought to investigate inflammation-related aberrant DNA methylation in CF twins and to determine to what extent acquired methylation changes may be associated with lung cancer. Blood-based genome-wide DNA methylation analysis was performed to compare the DNA methylomes of monozygotic twins, from the European CF Twin and Sibling Study with various degrees of disease severity. Putatively inflammation-related and differentially methylated positions were selected from a large lung cancer case-control study and investigated in blood by targeted bisulphite next-generation-sequencing. An inflammation-related locus located in the Plakophilin-3 (PKP3) gene was functionally analysed regarding promoter and enhancer activity in presence and absence of methylation using luciferase reporter assays. We confirmed in a unique cohort that monozygotic twins, even if clinically discordant, have only minor differences in global DNA methylation patterns and blood cell composition. Further, we determined the most differentially methylated positions, a high proportion of which are blood cell-type-specific, whereas others may be acquired and thus have potential relevance in the context of inflammation as lung cancer risk factors. We identified a sequence in the gene body of PKP3 which is hypermethylated in blood from CF twins with severe phenotype and highly variably methylated in lung cancer patients and controls, independent of known clinical parameters, and showed that this region exhibits methylation-dependent promoter activity in lung epithelial cells.
Collapse
Affiliation(s)
| | | | - Yassen Assenov
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Wolfgang Hagmann
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadja Zaborsky
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria.,Cancer Cluster Salzburg, Salzburg, Austria
| | | | - Anna Strobl
- Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - Frauke Stanke
- Clinical Research Group, Clinic for Pediatric Pneumology, Allergology and NeonatologyClinic for Pediatric Pneumology, Allergology and Neonatology, Hannover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover, Germany
| | - Thomas Muley
- Translational Research Unit, Thoraxklinik Heidelberg, University of Heidelberg, Germany.,Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Christoph Plass
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Burkhard Tümmler
- Clinical Research Group, Clinic for Pediatric Pneumology, Allergology and NeonatologyClinic for Pediatric Pneumology, Allergology and Neonatology, Hannover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover, Germany
| | - Angela Risch
- Department of Biosciences, University of Salzburg, Salzburg, Austria.,Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Cancer Cluster Salzburg, Salzburg, Austria.,Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| |
Collapse
|
|
6
|
Gao L, Li X, Guo Q, Nie X, Hao Y, Liu Q, Liu J, Zhu L, Yan L, Lin B. Identification of PKP 2/3 as potential biomarkers of ovarian cancer based on bioinformatics and experiments. Cancer Cell Int 2020; 20:509. [PMID: 33088217 PMCID: PMC7568375 DOI: 10.1186/s12935-020-01602-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 10/12/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Plakophilins (PKPs) are widely involved in gene transcription, translation, and signal transduction, playing a crucial role in tumorigenesis and progression. However, the function and potential mechanism of PKP1/2/3 in ovarian cancer (OC) remains unclear. It's of great value to explore the expression and prognostic values of PKP1/2/3 and their potential mechanisms, immune infiltration in OC. METHODS The expression levels, prognostic values and genetic variations of PKP1/2/3 in OC were explored by various bioinformatics tools and databases, and PKP2/3 were selected for further analyzing their regulation network and immune infiltration. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) enrichment were also conducted. Finally, the expression and prognosis of PKP2 were validated by immunohistochemistry. RESULTS The expression level and prognosis of PKP1 showed little significance in ovarian cancer, and the expression of PKP2/3 mRNA and protein were upregulated in OC, showing significant correlations with poor prognosis of OC. Functional enrichment analysis showed that PKP2/3 and their correlated genes were significantly enriched in adaptive immune response, cytokine receptor activity, organization of cell-cell junction and extracellular matrix; KEGG analysis showed that PKP2/3 and their significantly correlated genes were involved in signaling pathways including cytokine-mediated signaling pathway, receptor signaling pathway and pathways in cancer. Moreover, PKP2/3 were correlated with lymphocytes and immunomodulators. We confirmed that high expression of PKP2 was significantly associated with advanced stage, poor differentiation and poor prognosis of OC patients. CONCLUSION Members of plakophilins family showed various degrees of abnormal expressions and prognostic values in ovarian cancer. PKP2/3 played crucial roles in tumorigenesis, aggressiveness, malignant biological behavior and immune infiltration of OC, and can be regarded as potential biomarker for early diagnosis and prognosis evaluation in OC.
Collapse
Affiliation(s)
- Lingling Gao
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| | - Xiao Li
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| | - Qian Guo
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| | - Xin Nie
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| | - Yingying Hao
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| | - Qing Liu
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| | - Juanjuan Liu
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| | - Liancheng Zhu
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| | - Limei Yan
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| | - Bei Lin
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning China
| |
Collapse
|
|
7
|
|
|
8
|
Yang C, Chen F, Wang S, Xiong B. Circulating Tumor Cells in Gastrointestinal Cancers: Current Status and Future Perspectives. Front Oncol 2019; 9:1427. [PMID: 31921680 PMCID: PMC6923205 DOI: 10.3389/fonc.2019.01427] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/29/2019] [Indexed: 12/24/2022] Open
Abstract
Circulating tumor cells (CTCs), which are now defined as the "break away" cancer cells that derive from primary- or metastatic-tumor sites and present in the bloodstream, are considered to be the precursors of metastases. Considering the key role of CTCs in cancer progression, researchers are committed to analyze them in the past decades and many technologies have been proposed for achieving CTCs isolation and characterization with highly sensitivity and specificity until now. On this basis, clinicians gradually realize the clinical values of CTCs' detection through various clinical studies. As a "liquid biopsy," CTCs' detection and measurement can supply important information for predicting patient's survival, monitoring of response/resistance, assessment of minimal residual disease, evaluating distant metastasis, and sometimes, customizing therapy choices. Nowadays, eliminating CTCs of the blood circulation has been regarded as a promising method to prevent tumor metastasis. However, research on CTCs still faces many challenges. Herein, we present an overview to discuss the current concept of CTCs, summarize the available techniques for CTCs detection, and provide an update on the clinical significance of CTCs in gastrointestinal malignancies, especially focus on gastric and colorectal cancer.
Collapse
Affiliation(s)
- Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.,Hubei Cancer Clinical Study Center, Wuhan, China
| | - Fangfang Chen
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.,Hubei Cancer Clinical Study Center, Wuhan, China.,Department of Breast and Thyroid Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.,Hubei Cancer Clinical Study Center, Wuhan, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.,Hubei Cancer Clinical Study Center, Wuhan, China
| |
Collapse
|
|
9
|
Lim V, Zhu H, Diao S, Hu L, Hu J. PKP3 interactions with MAPK-JNK-ERK1/2-mTOR pathway regulates autophagy and invasion in ovarian cancer. Biochem Biophys Res Commun 2018; 508:646-653. [PMID: 30527804 DOI: 10.1016/j.bbrc.2018.11.163] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 11/26/2018] [Indexed: 12/15/2022]
Abstract
Armadillo-related proteins function in both signal transduction and cell adhesion, it also plays a central role in tumorigenesis. Plakophilin 3 (PKP3) is a member of the armadillo protein family. PKP3 has demonstrated a role in melanoma, breast cancer, gastric cancer, and other kind of cancers; however its role in ovarian cancer was not fully understood. In this study we explored the function and mechanisms of PKP3 in ovarian cancer. An elevated level of PKP3 was found in ovarian cancer tissues compared with normal tissues. PKP3 also modulate cellular proliferation and invasion in ovarian cancer. The ability of cellular proliferation, formation, and invasion was significantly decreased after the silencing of PKP3 in SKOV3 cells. While an over-expression of PKP3 in A2780 cells up-regulates the ability of cellular proliferation, formation, and invasion. As for the mechanism of PKP3, mTOR pathway was activated to regulate autophagy according to the interaction of PKP3 with the upstream of MAPK pathway. The result of this study support PKP3 as the oncogene candidate and a potential target for the treatment of ovarian cancer.
Collapse
Affiliation(s)
- Vincent Lim
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hongtao Zhu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Shuai Diao
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Lina Hu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Jianguo Hu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| |
Collapse
|
|
10
|
Likhitrattanapisal S, Tipanee J, Janvilisri T. Meta-analysis of gene expression profiles identifies differential biomarkers for hepatocellular carcinoma and cholangiocarcinoma. Tumour Biol 2016; 37:12755-12766. [PMID: 27448818 DOI: 10.1007/s13277-016-5186-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 07/13/2016] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the members of hepatobiliary diseases. Both types of cancer often exert high levels of similarity in terms of phenotypic characteristics, thus leading to difficulties in HCC and CCA differential diagnoses. In this study, a transcriptome meta-analysis was performed on HCC and CCA microarray data to identify differential transcriptome networks and potential biomarkers for HCC and CCA. Raw data from nine gene expression profiling datasets, consisting of 1,185 samples in total, were methodologically compiled and analyzed. To evaluate differentially expressed (DE) genes in HCC and CCA, the levels of gene expression were compared between cancer and its normal counterparts (i.e., HCC versus normal liver and CCA versus normal bile duct) using t test (P < 0.05) and k-fold validation. A total of 226 DE genes were specific to HCC, 249 DE genes specific to CCA, and 41 DE genes in both HCC and CCA. Gene ontology and pathway enrichment analyses revealed different patterns between functional transcriptome networks of HCC and CCA. Cell cycle and glycolysis/gluconeogenesis pathways were exclusively dysregulated in HCC whereas complement and coagulation cascades as well as glycine, serine, and threonine metabolism were prodominantly differentially expressed in CCA. Our meta-analysis revealed distinct dysregulation in transcriptome networks between HCC and CCA. Certain genes in these networks were discussed in the context of HCC and CCA transition, unique characteristics of HCC and CCA, and their potentials as HCC and CCA differential biomarkers.
Collapse
Affiliation(s)
| | - Jaitip Tipanee
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
| |
Collapse
|
|
11
|
Yang C, Fischer-Kešo R, Schlechter T, Ströbel P, Marx A, Hofmann I. Plakophilin 1-deficient cells upregulate SPOCK1: implications for prostate cancer progression. Tumour Biol 2015; 36:9567-77. [DOI: 10.1007/s13277-015-3628-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 05/31/2015] [Indexed: 12/19/2022] Open
|
|
12
|
Robichaux JP, Hallett RM, Fuseler JW, Hassell JA, Ramsdell AF. Mammary glands exhibit molecular laterality and undergo left-right asymmetric ductal epithelial growth in MMTV-cNeu mice. Oncogene 2015; 34:2003-10. [PMID: 24909172 PMCID: PMC4261057 DOI: 10.1038/onc.2014.149] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 04/01/2014] [Accepted: 04/21/2014] [Indexed: 02/07/2023]
Abstract
Significant left-right (L-R) differences in tumor incidence and disease outcome occur for cancers of paired organs, including the breasts; however, the basis for this laterality is unknown. Here, we show that despite their morphologic symmetry, left versus right mammary glands in wild-type mice have baseline differences in gene expression that are L-R independently regulated during pubertal development, including genes that regulate luminal progenitor cell renewal, luminal cell differentiation, mammary tumorigenesis, tamoxifen sensitivity and chemotherapeutic resistance. In MMTV-cNeu(Tg/Tg) mice, which model HER2/Neu-amplified breast cancer, baseline L-R differences in mammary gene expression are amplified, sustained or inverted in a gene-specific manner and the mammary ductal epithelium undergoes L-R asymmetric growth and patterning. Comparative genomic analysis of mouse L-R mammary gene expression profiles with gene expression profiles of human breast tumors revealed significant linkage between right-sided gene expression and decreased breast cancer patient survival. Collectively, these findings are the first to demonstrate that mammary glands are lateralized organs, and, moreover, that mammary glands have L-R differential susceptibility to HER2/Neu oncogene-mediated effects on ductal epithelial growth and differentiation. We propose that intrinsic molecular laterality may have a role in L-R asymmetric breast tumor incidence and, furthermore, that interplay between the L-R molecular landscape and oncogene activity may contribute to the differential disease progression and patient outcome that are associated with tumor situs.
Collapse
Affiliation(s)
- Jacqulyne P. Robichaux
- Department of Regenerative Medicine and Cell Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425
| | - Robin M. Hallett
- Department of Biochemistry and Biomedical Sciences, Centre for Functional Genomics, McMaster University, Ontario, Canada
| | - John W. Fuseler
- Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208
| | - John A. Hassell
- Department of Biochemistry and Biomedical Sciences, Centre for Functional Genomics, McMaster University, Ontario, Canada
| | - Ann F. Ramsdell
- Department of Regenerative Medicine and Cell Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425
- Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208
- Program In Women’s and Gender Studies, College of Arts and Sciences, University of South Carolina, Columbia, SC 29208
| |
Collapse
|
|
13
|
Broussard JA, Getsios S, Green KJ. Desmosome regulation and signaling in disease. Cell Tissue Res 2015; 360:501-12. [PMID: 25693896 DOI: 10.1007/s00441-015-2136-5] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 01/21/2015] [Indexed: 01/10/2023]
Abstract
Desmosomes are cell-cell adhesive organelles with a well-known role in forming strong intercellular adhesion during embryogenesis and in adult tissues subject to mechanical stress, such as the heart and skin. More recently, desmosome components have also emerged as cell signaling regulators. Loss of expression or interference with the function of desmosome molecules results in diseases of the heart and skin and contributes to cancer progression. However, the underlying molecular mechanisms that result in inherited and acquired disorders remain poorly understood. To address this question, researchers are directing their studies towards determining the functions that occur inside and outside of the junctions and the extent to which functions are adhesion-dependent or independent. This review focuses on recent discoveries that provide insights into the role of desmosomes and desmosome components in cell signaling and disease; wherever possible, we address molecular functions within and outside of the adhesive structure.
Collapse
Affiliation(s)
- Joshua A Broussard
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | | | | |
Collapse
|
|
14
|
Todorovic V, Koetsier JL, Godsel LM, Green KJ. Plakophilin 3 mediates Rap1-dependent desmosome assembly and adherens junction maturation. Mol Biol Cell 2014; 25:3749-64. [PMID: 25208567 PMCID: PMC4230782 DOI: 10.1091/mbc.e14-05-0968] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Desmosomal Armadillo family member Pkp3 is established as a coordinator of desmosome and adherens junction assembly and maturation through its physical and functional association with Rap1. It thus functions in a manner distinct from the closely related Pkp2. The pathways driving desmosome and adherens junction assembly are temporally and spatially coordinated, but how they are functionally coupled is poorly understood. Here we show that the Armadillo protein plakophilin 3 (Pkp3) mediates both desmosome assembly and E-cadherin maturation through Rap1 GTPase, thus functioning in a manner distinct from the closely related plakophilin 2 (Pkp2). Whereas Pkp2 and Pkp3 share the ability to mediate the initial phase of desmoplakin (DP) accumulation at sites of cell–cell contact, they play distinct roles in later steps: Pkp3 is required for assembly of a cytoplasmic population of DP-enriched junction precursors, whereas Pkp2 is required for transfer of the precursors to the membrane. Moreover, Pkp3 forms a complex with Rap1 GTPase, promoting its activation and facilitating desmosome assembly. We show further that Pkp3 deficiency causes disruption of an E-cadherin/Rap1 complex required for adherens junction sealing. These findings reveal Pkp3 as a coordinator of desmosome and adherens junction assembly and maturation through its functional association with Rap1.
Collapse
Affiliation(s)
- Viktor Todorovic
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Jennifer L Koetsier
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Lisa M Godsel
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Kathleen J Green
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 R.H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| |
Collapse
|
|
15
|
Plakophilin-associated RNA-binding proteins in prostate cancer and their implications in tumor progression and metastasis. Virchows Arch 2013; 463:379-90. [PMID: 23881279 DOI: 10.1007/s00428-013-1452-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 07/01/2013] [Accepted: 07/08/2013] [Indexed: 01/04/2023]
Abstract
Both plakophilins (PKP) 1 and 3 play a role in the progression of prostate cancer. The RNA-binding proteins (RBPs) GAP-SH3-binding protein (G3BP), fragile-X-related protein 1 (FXR1), poly(A)-binding protein, cytoplasmic 1 (PABPC1), and up-frameshift factor 1 (UPF1) are associated with PKP3. All these RBPs have an impact on RNA metabolism. Until recently, the PKP-associated RBPs have not been analyzed in prostate cancer. In the current study, we showed by affinity purification that the PKP3-associated RBPs were also binding partners of PKP1. We examined the expression of PKP1/3-associated RBPs and PKP1/3 in prostate cell lines, tumor-free prostate, and 136 prostatic adenocarcinomas by immunofluorescence and immunoblot. All four RBPs G3BP, FXR1, UPF1, and PABPC1 were expressed in the glandular epithelium of the normal prostate. PKP1 and FXR1 were strongly reduced in tumor tissues with Gleason score >7 and diminished expression of PKP1 and FXR1 also appeared to be associated with a metastatic phenotype. Additionally, the predominant nuclear localization of UPF1 in normal glandular cells and low grade tumors was switched to a more cytoplasmic pattern in carcinomas with Gleason score >7. Our findings suggest that PKP1 and FXR1 may have a tumor-suppressive function and are downregulated in more aggressive tumors. Collectively, PKP1/3-associated RBPs FXR1 and UPF1 may have a functional role in prostate cancer progression and metastasis and highlight the potential importance of posttranscriptional regulation of gene expression and nonsense-mediated decay in cancer.
Collapse
|
|
16
|
Wolf A, Rietscher K, Glaß M, Hüttelmaier S, Schutkowski M, Ihling C, Sinz A, Wingenfeld A, Mun A, Hatzfeld M. Insulin signaling via Akt2 switches plakophilin 1 function from stabilizing cell adhesion to promoting cell proliferation. J Cell Sci 2013; 126:1832-44. [PMID: 23444369 DOI: 10.1242/jcs.118992] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Downregulation of adherens junction proteins is a frequent event in carcinogenesis. How desmosomal proteins contribute to tumor formation by regulating the balance between adhesion and proliferation is not well understood. The desmosomal protein plakophilin 1 can increase intercellular adhesion by recruiting desmosomal proteins to the plasma membrane or stimulate proliferation by enhancing translation rates. Here, we show that these dual functions of plakophilin 1 are regulated by growth factor signaling. Insulin stimulation induced the phosphorylation of plakophilin 1, which correlated with reduced intercellular adhesion and an increased activity of plakophilin 1 in the stimulation of translation. Phosphorylation was mediated by Akt2 at four motifs within the plakophilin 1 N-terminal domain. A plakophilin 1 phospho-mimetic mutant revealed reduced intercellular adhesion and accumulated in the cytoplasm, where it increased translation and proliferation rates and conferred the capacity of anchorage-independent growth. The cytoplasmic accumulation was mediated by the stabilization of phosphorylated plakophilin 1, which displayed a considerably increased half-life, whereas non-phosphorylated plakophilin 1 was more rapidly degraded. Our data indicate that upon activation of growth factor signaling, plakophilin 1 switches from a desmosome-associated growth-inhibiting to a cytoplasmic proliferation-promoting function. This supports the view that the deregulation of plakophilin 1, as observed in several tumors, directly contributes to hyperproliferation and carcinogenesis in a context-dependent manner.
Collapse
Affiliation(s)
- Annika Wolf
- Institute of Molecular Medicine, Division of Pathobiochemistry, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Valladares-Ayerbes M, Blanco-Calvo M, Reboredo M, Lorenzo-Patiño MJ, Iglesias-Díaz P, Haz M, Díaz-Prado S, Medina V, Santamarina I, Pértega S, Figueroa A, Antón-Aparicio LM. Evaluation of the adenocarcinoma-associated gene AGR2 and the intestinal stem cell marker LGR5 as biomarkers in colorectal cancer. Int J Mol Sci 2012; 13:4367-4387. [PMID: 22605983 PMCID: PMC3344219 DOI: 10.3390/ijms13044367] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 03/20/2012] [Accepted: 03/23/2012] [Indexed: 01/06/2023] Open
Abstract
We aim to estimate the diagnostic performances of anterior gradient homolog-2 (AGR2) and Leucine-rich repeat-containing-G-protein-coupled receptor 5 (LGR5) in peripheral blood (PB) as mRNA biomarkers in colorectal cancer (CRC) and to explore their prognostic significance. Real-time PCR was used to analyze AGR2 and LGR5 in 54 stages I-IV CRC patients and 19 controls. Both mRNAs were significantly increased in PB from CRC patients compared to controls. The area under the receiver-operating characteristic curves were 0.722 (p = 0.006), 0.376 (p = 0.123) and 0.767 (p = 0.001) for AGR2, LGR5 and combined AGR2/LGR5, respectively. The AGR2/LGR5 assay resulted in 67.4% sensitivity and 94.7% specificity. AGR2 correlated with pT3–pT4 and high-grade tumors. LGR5 correlated with metastasis, R2 resections and high-grade. The progression-free survival (PFS) of patients with high AGR2 was reduced (p = 0.037; HR, 2.32), also in the stage I-III subgroup (p = 0.046). LGR5 indicated a poor prognosis regarding both PFS (p = 0.007; HR, 1.013) and overall survival (p = 0.045; HR, 1.01). High AGR2/LGR5 was associated with poor PFS (p = 0.014; HR, 2.8) by multivariate analysis. Our findings indicate that the assessment of AGR2 and LGR5 in PB might reflect the presence of circulating tumor cells (CTC) and stem cell like CTC in CRC. Increased AGR2 and LGR5 are associated with poor outcomes.
Collapse
Affiliation(s)
- Manuel Valladares-Ayerbes
- Medical Oncology Department, La Coruña University Hospital, Servicio Galego de Saúde (SERGAS), As Xubias, 84. PC 15006, La Coruña, Spain; E-Mails: (M.R.); (L.M.A.-A.)
- Translational Cancer Research Lab, Biomedical Research Institute (INIBIC), Carretera del Pasaje, s/n. PC 15006, La Coruña, Spain; E-Mails: (M.B.-C.); (M.H.); (V.M.); (I.S.); (A.F.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel. +34-981178000 (ext. 292848); Fax: +34-981178273
| | - Moisés Blanco-Calvo
- Translational Cancer Research Lab, Biomedical Research Institute (INIBIC), Carretera del Pasaje, s/n. PC 15006, La Coruña, Spain; E-Mails: (M.B.-C.); (M.H.); (V.M.); (I.S.); (A.F.)
| | - Margarita Reboredo
- Medical Oncology Department, La Coruña University Hospital, Servicio Galego de Saúde (SERGAS), As Xubias, 84. PC 15006, La Coruña, Spain; E-Mails: (M.R.); (L.M.A.-A.)
| | - María J. Lorenzo-Patiño
- Pathology Department, La Coruña University Hospital, Servicio Galego de Saúde (SERGAS), As Xubias, 84. PC 15006, La Coruña, Spain; E-Mails: (M.J.L.-P.); (P.I.-D.)
| | - Pilar Iglesias-Díaz
- Pathology Department, La Coruña University Hospital, Servicio Galego de Saúde (SERGAS), As Xubias, 84. PC 15006, La Coruña, Spain; E-Mails: (M.J.L.-P.); (P.I.-D.)
| | - Mar Haz
- Translational Cancer Research Lab, Biomedical Research Institute (INIBIC), Carretera del Pasaje, s/n. PC 15006, La Coruña, Spain; E-Mails: (M.B.-C.); (M.H.); (V.M.); (I.S.); (A.F.)
| | - Silvia Díaz-Prado
- Tissue Engineering and Cellular Therapy Lab, INIBIC, Carretera del Pasaje, s/n. PC 15006, La Coruña, Spain; E-Mail:
- Medicine Department, La Coruña University (UDC), Campus de Oza, s/n, PC 15006, La Coruña, Spain
| | - Vanessa Medina
- Translational Cancer Research Lab, Biomedical Research Institute (INIBIC), Carretera del Pasaje, s/n. PC 15006, La Coruña, Spain; E-Mails: (M.B.-C.); (M.H.); (V.M.); (I.S.); (A.F.)
| | - Isabel Santamarina
- Translational Cancer Research Lab, Biomedical Research Institute (INIBIC), Carretera del Pasaje, s/n. PC 15006, La Coruña, Spain; E-Mails: (M.B.-C.); (M.H.); (V.M.); (I.S.); (A.F.)
| | - Sonia Pértega
- Biostatistics and Clinical Epidemiology Unit, La Coruña University Hospital, Servicio Galego de Saúde (SERGAS), As Xubias 84, PC 15006, La Coruña, Spain; E-Mail:
| | - Angélica Figueroa
- Translational Cancer Research Lab, Biomedical Research Institute (INIBIC), Carretera del Pasaje, s/n. PC 15006, La Coruña, Spain; E-Mails: (M.B.-C.); (M.H.); (V.M.); (I.S.); (A.F.)
| | - Luis M. Antón-Aparicio
- Medical Oncology Department, La Coruña University Hospital, Servicio Galego de Saúde (SERGAS), As Xubias, 84. PC 15006, La Coruña, Spain; E-Mails: (M.R.); (L.M.A.-A.)
- Medicine Department, La Coruña University (UDC), Campus de Oza, s/n, PC 15006, La Coruña, Spain
| |
Collapse
|
|
18
|
Hakai reduces cell-substratum adhesion and increases epithelial cell invasion. BMC Cancer 2011; 11:474. [PMID: 22051109 PMCID: PMC3229560 DOI: 10.1186/1471-2407-11-474] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Accepted: 11/03/2011] [Indexed: 12/14/2022] Open
Abstract
Background The dynamic regulation of cell-cell adhesions is crucial for developmental processes, including tissue formation, differentiation and motility. Adherens junctions are important components of the junctional complex between cells and are necessary for maintaining cell homeostasis and normal tissue architecture. E-cadherin is the prototype and best-characterized protein member of adherens junctions in mammalian epithelial cells. Regarded as a tumour suppressor, E-cadherin loss is associated with poor prognosis in carcinoma. The E3 ubiquitin-ligase Hakai was the first reported posttranslational regulator of the E-cadherin complex. Hakai specifically targetted E-cadherin for internalization and degradation and thereby lowered epithelial cell-cell contact. Hakai was also implicated in controlling proliferation, and promoted cancer-related gene expression by increasing the binding of RNA-binding protein PSF to RNAs encoding oncogenic proteins. We sought to investigate the possible implication of Hakai in cell-substratum adhesions and invasion in epithelial cells. Methods Parental MDCK cells and MDCK cells stably overexpressing Hakai were used to analyse cell-substratum adhesion and invasion capabilities. Western blot and immunofluoresecence analyses were performed to assess the roles of Paxillin, FAK and Vinculin in cell-substratum adhesion. The role of the proteasome in controlling cell-substratum adhesion was studied using two proteasome inhibitors, lactacystin and MG132. To study the molecular mechanisms controlling Paxillin expression, MDCK cells expressing E-cadherin shRNA in a tetracycline-inducible manner was employed. Results Here, we present evidence that implicate Hakai in reducing cell-substratum adhesion and increasing epithelial cell invasion, two hallmark features of cancer progression and metastasis. Paxillin, an important protein component of the cell-matrix adhesion, was completely absent from focal adhesions and focal contacts in Hakai-overexpressing MDCK cells. The expression of Paxillin was found to be regulated by a proteasome-independent mechanism, possibly due to the decreased abundance of E-cadherin. Conclusions Taken together, these results suggest that Hakai may be involved in two hallmark aspects of tumour progression, the lowering cell-substratum adhesion and the enhancement of cell invasion.
Collapse
|