CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology

DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field.

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Opioids trigger breast cancer metastasis through E-Cadherin downregulation and STAT3 activation promoting epithelial-mesenchymal transition

10.1101/443663 ◽

2018 ◽

Author(s):

Sabrina Tripolt ◽

Vanessa M. Knab ◽

Heidi A. Neubauer ◽

Dominik P. Elmer ◽

Fritz Aberger ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Cancer Biology ◽

Cancer Metastasis ◽

Kinase Inhibitor ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Metastasis ◽

Mesenchymal Transition ◽

Stat3 Signaling ◽

E Cadherin

AbstractThe opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental facts exist. Expression of δ-opioid receptors (DORs) correlates with poor prognosis for breast cancer (BCa) patients, but mechanism and genetic/pharmacologic proof of key changes in opioid-triggered cancer biology are lacking. We show that oncogenic STAT3 signaling and E-Cadherin downregulation are triggered by opioid-ligated DORs, promoting metastasis. Human and murine transplanted BCa cells (MDA-MB-231, 4T1) displayed enhanced metastasis upon opioid-induced DOR stimulation, and DOR-antagonist blocked metastasis. Opioid-exposed BCa cells showed enhanced migration, STAT3 activation, down-regulation of E-Cadherin and expression of epithelial-mesenchymal transition (EMT) markers. STAT3 knockdown or upstream inhibition through the JAK1/2 kinase inhibitor ruxolitinib prevented opioid-induced BCa cell metastasis and migration. We conclude that opioids trigger metastasis through oncogenic JAK1/2-STAT3 signaling.

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Cooperation of Cancer Stem Cell Properties and Epithelial-Mesenchymal Transition in the Establishment of Breast Cancer Metastasis

Journal of Oncology ◽

10.1155/2011/591427 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 30

Author(s):

Tetsu Hayashida ◽

Hiromitsu Jinno ◽

Yuko Kitagawa ◽

Masaki Kitajima

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Breast Cancer Metastasis ◽

Cell Junctions ◽

Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon.

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Increased Expressions of Matrix Metalloproteinases (MMPs) in Prostate Cancer Tissues of Men with Type 2 Diabetes

Biomedicines ◽

10.3390/biomedicines8110507 ◽

2020 ◽

Vol 8 (11) ◽

pp. 507

Author(s):

Andras Franko ◽

Lucia Berti ◽

Jörg Hennenlotter ◽

Steffen Rausch ◽

Marcus O. Scharpf ◽

...

Keyword(s):

Prostate Cancer ◽

Type 2 Diabetes ◽

Matrix Metalloproteinases ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Prostate Tissue ◽

Nuclear Antigen ◽

Gene Expressions ◽

Mesenchymal Transition

Type 2 diabetes (T2D) is associated with worse prognosis of prostate cancer (PCa). The molecular mechanisms behind this association are still not fully understood. The aim of this study was to identify key factors, which contribute to the more aggressive PCa phenotype in patients with concurrent T2D. Therefore, we investigated benign and PCa tissue of PCa patients with and without diabetes using real time qPCR. Compared to patients without diabetes, patients with T2D showed a decreased E-cadherin/N-cadherin (CDH1/CDH2) ratio in prostate tissue, indicating a switch of epithelial-mesenchymal transition (EMT), which is a pivotal process in carcinogenesis. In addition, the gene expression levels of matrix metalloproteinases (MMPs) and CC chemokine ligands (CCLs) were higher in prostate samples of T2D patients. Next, prostate adenocarcinoma PC3 cells were treated with increasing glucose concentrations to replicate hyperglycemia in vitro. In these cells, high glucose induced expressions of MMPs and CCLs, which showed significant positive associations with the proliferation marker proliferating cell nuclear antigen (PCNA). These results indicate that in prostate tissue of men with T2D, hyperglycemia may induce EMT, increase MMP and CCL gene expressions, which in turn activate invasion and inflammatory processes accelerating the progression of PCa.

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Abstract 3441: Cross-species expression profiling identifies Forkhead-Box Q1 as a promoter of epithelial-mesenchymal transition and breast cancer metastasis

10.1158/1538-7445.am2011-3441 ◽

2011 ◽

Cited By ~ 1

Author(s):

Haijun Zhang ◽

Fanyan Meng ◽

Gang Liu ◽

Bin Zhang ◽

Jun Zhu ◽

...

Keyword(s):

Breast Cancer ◽

Expression Profiling ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Metastasis ◽

Mesenchymal Transition ◽

Forkhead Box

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Abstract P1-05-04: A novel mechanism of epithelial-mesenchymal transition in breast cancer metastasis: Involvement of prostanoid receptor

10.1158/1538-7445.sabcs15-p1-05-04 ◽

2016 ◽

Author(s):

A Kwong ◽

MT Siu ◽

I Cheuk ◽

JC Ho ◽

J Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Metastasis ◽

Mesenchymal Transition ◽

Prostanoid Receptor

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miR-214 inhibits epithelial–mesenchymal transition of breast cancer cells via downregulation of RNF8

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmz067 ◽

2019 ◽

Vol 51 (8) ◽

pp. 791-798 ◽

Cited By ~ 3

Author(s):

Lu Min ◽

Chuanyang Liu ◽

Jingyu Kuang ◽

Xiaomin Wu ◽

Lingyun Zhu

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Metastasis ◽

Breast Cancer Patients ◽

Mesenchymal Transition ◽

Proliferation And Invasion

Abstract MicroRNAs (miRNAs) are a class of endogenous noncoding genes that regulate gene expression at the posttranscriptional level. In recent decades, miRNAs have been reported to play important roles in tumor growth and metastasis, while some reported functions of a specific miRNA in tumorigenesis are contradictory. In this study, we reevaluated the role of miR-214, which has been reported to serve as an oncogene or anti-oncogene in breast cancer metastasis. We found that miR-214 inhibited breast cancer via targeting RNF8, a newly identified regulator that could promote epithelial–mesenchymal transition (EMT). Specifically, the survival rate of breast cancer patients was positively correlated with miR-214 levels and negatively correlated with RNF8 expression. The overexpression of miR-214 inhibited cell proliferation and invasion of breast cancer, while suppression of miR-214 by chemically modified antagomir enhanced the proliferation and invasion of breast cancer cells. Furthermore, miR-214 could modulate the EMT process via downregulating RNF8. To our knowledge, this is the first report that reveals the role of the miR-214–RNF8 axis in EMT, and our results demonstrate a novel mechanism for miR-214 acting as a tumor suppressor through the regulation of EMT.

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Brucine suppresses breast cancer metastasis via inhibiting epithelial mesenchymal transition and matrix metalloproteinases expressions

Chinese Journal of Integrative Medicine ◽

10.1007/s11655-017-2805-1 ◽

2017 ◽

Vol 24 (1) ◽

pp. 40-46 ◽

Cited By ~ 7

Author(s):

Miao Li ◽

Ping Li ◽

Mei Zhang ◽

Feng Ma

Keyword(s):

Breast Cancer ◽

Matrix Metalloproteinases ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Metastasis ◽

Mesenchymal Transition

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Breast Cancer Metastasis: Role of Tumor Microenvironment and Resident Macropahges

Defence Life Science Journal ◽

10.14429/dlsj.1.10058 ◽

2016 ◽

Vol 1 (1) ◽

pp. 48

Author(s):

Khemraj Singh Baghel ◽

Smrati Bhadauria

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

The Body ◽

Tissue Remodelling ◽

Mesenchymal Transition

Metastatic breast cancer is a stage of breast cancer wherever the disease has spread to distant parts of the body. Onset of metastasis is one of the biggest obstacles to the successful treatment of cancer. The potential of a tumor cell to metastasize profoundly depends on its microenvironment, or “niche” interactions with local components. Macrophages provide tropic support to tumors. Resident macrophages contribute a set of common functions, including their capability to defend against microbial infections, to maintain normal cell turnover and tissue remodelling, and to help repair sites of injury. Macrophages are recruited into the tumor microenvironment where they differentiate to become Tumor-associated-macrophages (TAMs). TAMs are the most abundant subpopulation of tumor-stroma and actively drive cancer cell invasion and metastasis. Cancer metastasis is not solely regulated by the deregulation of metastasis promoting or suppressing genes in cancer cells. Recently the interaction between the stromal cells and cancer cells has been demonstrated to promote cancer metastasis. TAMs can advocate epithelial-mesenchymal transition of cancer cells. Loss of e-cadherin, a major phenomenon of epithelial to mesenchymal transition (EMT), reduces adhesiveness and releases cancer cells to distant (secondary) sites. A positive correlation between tumor progression and the expression of matrix metallo proteinases (MMPs) in tumor tissues has been demonstrated in numerous human and animal studies. The dynamic interactions of cancer-cells with TAMs actively promote invasion-metastasis cascade through intercellular-signalling-networks that need better elucidation.

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