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Open AccessArticle

The Promoting Effect of the Extracellular Matrix Peptide TNIIIA2 Derived from Tenascin-C in Colon Cancer Cell Infiltration

by Hideo Suzuki, Manabu Sasada, Sadahiro Kamiya, Yuka Ito, Hikaru Watanabe, Yuko Okada, Kazuma Ishibashi, Takuya Iyoda, Akinori Yanaka and Fumio Fukai

Int. J. Mol. Sci. 2017, 18(1), 181; https://doi.org/10.3390/ijms18010181 - 17 Jan 2017

Cited by 15 | Viewed by 6820

Abstract

The extracellular matrix (ECM) molecule tenascin C (TNC) is known to be highly expressed under various pathological conditions such as inflammation and cancer. It has been reported that the expression of TNC is correlated with the malignant potential of cancer. In our laboratory, [...] Read more.

The extracellular matrix (ECM) molecule tenascin C (TNC) is known to be highly expressed under various pathological conditions such as inflammation and cancer. It has been reported that the expression of TNC is correlated with the malignant potential of cancer. In our laboratory, it was found that the peptide derived from the alternative splicing domain A2 in TNC, termed TNIIIA2, has been shown to influence a variety of cellular processes, such as survival, proliferation, migration, and differentiation. In this study, we investigated the effect of TNC/TNIIIA2 on the invasion and metastasis of colon cancer cells, Colon26-M3.1, or PMF-Ko14, using an in vitro and in vivo experimental system. The degree of cell invasion was increased by the addition of TNC and TNIIIA2 in a dose-dependent manner. The invasion by TNC and TNIIIA2 were suppressed by an MMP inhibitor or TNIIIA2-blocking antibody. In an in vivo experiment, pulmonary metastasis was promoted conspicuously by the addition of TNIIIA2. In this study, we found that colon cancer cell invasion and metastasis was accelerated by TNC/TNIIIA2 via MMP induction. This result suggests the possibility of a new strategy targeting TNC/TNIIIA2 for colon cancer. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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12237 KiB

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Genome-Wide Screen of miRNAs and Targeting mRNAs Reveals the Negatively Regulatory Effect of miR-130b-3p on PTEN by PI3K and Integrin β1 Signaling Pathways in Bladder Carcinoma

by Mengxin Lv, Zhenyu Zhong, Hong Chi, Mengge Huang, Rong Jiang and Junxia Chen

Int. J. Mol. Sci. 2017, 18(1), 78; https://doi.org/10.3390/ijms18010078 - 31 Dec 2016

Cited by 22 | Viewed by 6237

Abstract

miRNAs have emerged as promising markers for tumors. However, the underlying mechanism of specific miRNAs in bladder cancer (BC) remains largely unknown. Here, a comprehensive miRNA/mRNA expression profile was executed by microarray assay for four pairs of bladder carcinoma and para-carcinoma tissues from [...] Read more.

miRNAs have emerged as promising markers for tumors. However, the underlying mechanism of specific miRNAs in bladder cancer (BC) remains largely unknown. Here, a comprehensive miRNA/mRNA expression profile was executed by microarray assay for four pairs of bladder carcinoma and para-carcinoma tissues from patients with grade 2 (G2) T2. A total of 99 miRNAs and 4416 mRNAs were discovered to be significantly differentially expressed in BC tissues compared with controls. Five microRNAs and two mRNAs were validated by qRT-PCR in 30 pairs of samples, including G1–G3/T1–T4. Subsequently, we constructed a network with the five miRNAs-target mRNAs; gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were utilized to recognize the functions and associated pathways. Moreover, we further found that miR-130b-3p was significantly up-regulated and negatively correlated with phosphatase and tensin homolog (PTEN) expression in bladder cancer tissues. Next, we demonstrated that miR-130b-3p might target PTEN through bioinformatics and dual-luciferase reporter assay. Finally, we showed that miR-130b-3p could down-regulate PTEN expression, which promoted proliferation, migration, invasion and rearranged cytoskeleton through the activation of the PI3K and integrin β1 signaling pathway in bladder cancer cells. Inversely, miR-130b-3p inhibitors induced apoptosis. Taken together, this research investigated, for the first time, miR-130b-3p by an incorporated analysis of microRNA/mRNA expressions of a genome-wide screen in BC. Our findings suggest that the miR-130b-3p/PTEN/integrin β1 axis could play a critical role in the progression and development of BC and that miR-130b-3p might be a valuable clinical marker and therapeutical target for BC patients. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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α6β4 Integrin Genetic Variations (A380T and R1281W) and Breast Cancer Risk in an Argentinian Population

by Karina Beatriz Acosta, Melina Noelia Lorenzini Campos, Susana Beatriz Etcheverry and Pedro Dario Zapata

Int. J. Mol. Sci. 2016, 17(10), 1540; https://doi.org/10.3390/ijms17101540 - 18 Oct 2016

Cited by 2 | Viewed by 4263

Abstract

The α6β4 integrin is composed of the α6 and β4 subunits that are encoded by the ITGα6 and the ITGβ4 genes, respectively. The α6β4 main function is to intervene in lamination and epithelia integrity maintenance by cell-matrix interactions. This integrin appears to have [...] Read more.

The α6β4 integrin is composed of the α6 and β4 subunits that are encoded by the ITGα6 and the ITGβ4 genes, respectively. The α6β4 main function is to intervene in lamination and epithelia integrity maintenance by cell-matrix interactions. This integrin appears to have importance in breast cancer malignancy, as well as other epithelial carcinomas. The aim of this work was to investigate the potential role of ITGα6 (A380T) and ITGβ4 (R1281W) genetic variations in breast cancer susceptibility, in a female population from the northeast region of Argentina (Misiones). We performed a case-control study of 85 breast cancer patients and 113 cancer-free controls. Genotyping was performed by RFLP-PCR. For ITGα6 (A380T) single nucleotide polymorphism, a high frequency of heterozygous genotype GA in cases compared to controls was observed, achieving values of 48% and 49%, respectively. No association between the A380T SNP and breast cancer development was found (Odds Ratio = 0.92; 95% Confidence Interval = 0.52–1.63; p = 0.884). In conclusion, we did not find evidence of an association between A380T (ITGα6) and the risk of developing breast cancer. The results represent the first report of these genetic variations in breast cancer; therefore, they are an important contribution to the literature. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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Open AccessArticle

β1 Integrin as a Prognostic and Predictive Marker in Triple-Negative Breast Cancer

by Hsin-Ling Yin, Chun-Chieh Wu, Chih-Hung Lin, Chee-Yin Chai, Ming-Feng Hou, Shu-Jyuan Chang, Hung-Pei Tsai, Wen-Chun Hung, Mei-Ren Pan and Chi-Wen Luo

Int. J. Mol. Sci. 2016, 17(9), 1432; https://doi.org/10.3390/ijms17091432 - 31 Aug 2016

Cited by 50 | Viewed by 7195

Abstract

Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying [...] Read more.

Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying the aggressive behaviors of TNBC is required for the design of individualized strategies and the elongation of overall survival duration. Here, we supported a positive correlation between β1 integrin and malignant behaviors such as cell migration, invasion, and drug resistance. We found that silencing of β1 integrin inhibited cell migration, invasion, and increased the sensitivity to anti-cancer drug. In contrast, activation of β1 integrin increased cell migration, invasion, and decreased the sensitivity to anti-cancer drug. Furthermore, we found that silencing of β1 integrin abolished Focal adhesion kinese (FAK) mediated cell survival. Overexpression of FAK could restore cisplatin-induced apoptosis in β1 integrin-depleted cells. Consistent to in vitro data, β1 integrin expression was also positively correlated with FAK (p = 0.031) in clinical tissue. More importantly, β1 integrin expression was significantly correlated with patient outcome. In summary, our study indicated that β1 integrin could regulate TNBC cells migration, invasion, drug sensitivity, and be a potential prognostic biomarker in TNBC patient survival. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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Review

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Open AccessReview

Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer

by Rehman Ata and Costin N. Antonescu

Int. J. Mol. Sci. 2017, 18(1), 189; https://doi.org/10.3390/ijms18010189 - 18 Jan 2017

Cited by 100 | Viewed by 14028

Abstract

Integrins are important regulators of cell survival, proliferation, adhesion and migration. Once activated, integrins establish a regulated link between the extracellular matrix and the cytoskeleton. Integrins have well-established functions in cancer, such as in controlling cell survival by engagement of many specific intracellular [...] Read more.

Integrins are important regulators of cell survival, proliferation, adhesion and migration. Once activated, integrins establish a regulated link between the extracellular matrix and the cytoskeleton. Integrins have well-established functions in cancer, such as in controlling cell survival by engagement of many specific intracellular signaling pathways and in facilitating metastasis. Integrins and associated proteins are regulated by control of transcription, membrane traffic, and degradation, as well as by a number of post-translational modifications including glycosylation, allowing integrin function to be modulated to conform to various cellular needs and environmental conditions. In this review, we examine the control of integrin function by cell metabolism, and the impact of this regulation in cancer. Within this context, nutrient sufficiency or deprivation is sensed by a number of metabolic signaling pathways such as AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) 1, which collectively control integrin function by a number of mechanisms. Moreover, metabolic flux through specific pathways also controls integrins, such as by control of integrin glycosylation, thus impacting integrin-dependent cell adhesion and migration. Integrins also control various metabolic signals and pathways, establishing the reciprocity of this regulation. As cancer cells exhibit substantial changes in metabolism, such as a shift to aerobic glycolysis, enhanced glucose utilization and a heightened dependence on specific amino acids, the reciprocal regulation of integrins and metabolism may provide important clues for more effective treatment of various cancers. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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Open AccessReview

Focal Adhesion Kinase: Insight into Molecular Roles and Functions in Hepatocellular Carcinoma

by Nadia Panera, Annalisa Crudele, Ilaria Romito, Daniela Gnani and Anna Alisi

Int. J. Mol. Sci. 2017, 18(1), 99; https://doi.org/10.3390/ijms18010099 - 5 Jan 2017

Cited by 56 | Viewed by 8067

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Due to the high incidence of post-operative recurrence after current treatments, the identification of new and more effective drugs is required. In previous years, new targetable genes/pathways involved in HCC pathogenesis [...] Read more.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Due to the high incidence of post-operative recurrence after current treatments, the identification of new and more effective drugs is required. In previous years, new targetable genes/pathways involved in HCC pathogenesis have been discovered through the help of high-throughput sequencing technologies. Mutations in TP53 and β-catenin genes are the most frequent aberrations in HCC. However, approaches able to reverse the effect of these mutations might be unpredictable. In fact, if the reactivation of proteins, such as p53 in tumours, holds great promise as anticancer therapy, there are studies arguing that chronic activation of these types of molecules may be deleterious. Thus, recently the efforts on potential targets have focused on actionable mutations, such as those occurring in the gene encoding for focal adhesion kinase (FAK). This tyrosine kinase, localized to cellular focal contacts, is over-expressed in a variety of human tumours, including HCC. Moreover, several lines of evidence demonstrated that FAK depletion or inhibition impair in vitro and in vivo HCC growth and metastasis. Here, we provide an overview of FAK expression and activity in the context of tumour biology, discussing the current evidence of its connection with HCC development and progression. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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2027 KiB

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Integrins in the Spotlight of Cancer

by Daniela Bianconi, Matthias Unseld and Gerald W. Prager

Int. J. Mol. Sci. 2016, 17(12), 2037; https://doi.org/10.3390/ijms17122037 - 6 Dec 2016

Cited by 119 | Viewed by 10173

Abstract

Integrins are heterodimeric cell surface receptors that bind to different extracellular ligands depending on their composition and regulate all processes which enable multicellular life. In cancer, integrins trigger and play key roles in all the features that were once described as the Hallmarks [...] Read more.

Integrins are heterodimeric cell surface receptors that bind to different extracellular ligands depending on their composition and regulate all processes which enable multicellular life. In cancer, integrins trigger and play key roles in all the features that were once described as the Hallmarks of Cancer. In this review, we will discuss the contribution of integrins to these hallmarks, including uncontrolled and limitless proliferation, invasion of tumor cells, promotion of tumor angiogenesis and evasion of apoptosis and resistance to growth suppressors, by highlighting the latest findings. Further on, given the paramount role of integrins in cancer, we will present novel strategies for integrin inhibition that are starting to emerge, promising a hopeful future regarding cancer treatment. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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Tension in Cancer

by Stefanie Löffek, Claus-Werner Franzke and Iris Helfrich

Int. J. Mol. Sci. 2016, 17(11), 1910; https://doi.org/10.3390/ijms17111910 - 16 Nov 2016

Cited by 14 | Viewed by 7179

Abstract

Integrins represent a large family of cell receptors that mediate adhesion to the extracellular matrix (ECM), thereby modulating a variety of cellular functions that are required for proliferation, migration, malignant conversion and invasiveness. During tumorigenesis the conversion of a tumor cell from sessile, [...] Read more.

Integrins represent a large family of cell receptors that mediate adhesion to the extracellular matrix (ECM), thereby modulating a variety of cellular functions that are required for proliferation, migration, malignant conversion and invasiveness. During tumorigenesis the conversion of a tumor cell from sessile, stationary phenotype to an invasive phenotype requires the ability of tumor cells to interact with their environment in order to transduce signals from the ECM into the cells. Hence, there is increasing evidence that changes in the composition, topography and tension of tumor matrix can be sensed by integrin receptors, leading to the regulation of intracellular signalling events which subsequently help to fuel cancer progression. The fact that intracellular signals perceived from integrin ligand binding impact on almost all steps of tumor progression, including tumor cell proliferation, survival, metastatic dissemination and colonization of a metastatic niche, renders integrins as ideal candidates for the development of therapeutic agents. In this review we summarize the role of integrins in cancer with the special focus on cancer therapies and the recent progress that has been made in the understanding of “integrin-induced tension in cancer”. Finally, we conclude with clinical evidence for the role of integrin-mediated mechanotransduction in the development of therapy-resistant tumors. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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