The COOH-terminus of the IGF-1Ec Isoform Enhances the Proliferation and Migration of Human MCF-7 Breast Cancer Cells

Christopoulos, Panagiotis; Papageorgiou, Efstathia; Petraki, Constantina; Koutsilieris, Michael

doi:10.21873/anticanres.11643

Cited by 3 publications

(9 citation statements)

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“…Mature IGF-I peptide represents the common bioactive product of all IGF-I isoforms (20,25) and multiple studies have shown that this peptide is involved in cell survival and apoptosis, as well as in the process of uncontrolled cell proliferation, which generally characterizes cancer development (7,26,27). These IGF-I functions have been shown to affect various types of human cancer cells, such as prostate, breast and osteosarcoma cells (5,(28)(29)(30)(31)(32), while IGF-I has also been shown to contribute to neovascularization (33), tumor aggressiveness and cancer cell migration (34).…”

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confidence: 99%

IGF-IEc Expression Is Associated With Advanced Differentiated Thyroid Cancer

et al. 2019

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Background/Aim: Recent knowledge implicates a differential expression of the insulin-like growth factor-I (IGF-I) mRNA splice variants (i.e., IGF-IEa, IGF-IEb and IGF-IEc) in cancerous tissues, implying possible specific roles of the encoded IGF-I protein isoforms in cancer biology. In particular, there is growing evidence that the IGF-IEc isoform may play a distinct biological role in various types of cancers. The present study investigated whether IGF-IEc expression is associated with a particular type of thyroid cancer. Materials and Methods: Formalinfixed paraffin-embedded tissue specimens of different types of thyroid cancers from 92 patients were assessed for IGF-IEc expression by immunohistochemistry. In addition, thyroid cancer biopsies of different TNM staging histological types were evaluated for mRNA expression of the IGF-IEc transcript by real-time polymerase chain reaction (PCR). Results: From the total number of 92 samples, 2 were anaplastic, 10 medullary, 4 hyperplasias of C-cells, 11 follicular, 5 hurtle cell carcinomas, 2 poorly differentiated, 5 nodular hyperplasias, 1 lymphoma and 52 were papillary thyroid cancers. The age of cancer diagnosis or tumor size did not significantly affect the IGF-IEc expression. Among all types of cancers, IGF-IEc was expressed in papillary differentiated thyroid cancer. Its expression/localization was mainly cytoplasmic and significantly associated with TNM staging and the presence of muscular and capsule cancerous invasion (p<0.05). Similarly, a differential profile was revealed regarding the mRNA expression of the IGF-IEc transcript, that exhibited a higher expression in aggressive compared to the non-aggressive papillary cancers. Conclusion: IGF-IEc isoform expression in thyroid cancer is positively associated with more advanced stages of papillary thyroid cancer.Thyroid cancer accounts for the 1% of all human neoplasias and is the most common endocrine cancer. Over the last decades, its rate has developed rapidly because of the multiple, congregate environmental factors and the rapid advances in diagnostic radiology tools that detect small size cancers, that otherwise would remain undiagnosed. Basically, thyroid cancer is classified in 4 main categories; the differentiated cancer (papillary and follicular thyroid cancer), the poorly differentiated, the medullary cancer, which derives from parafollicular C cells of thyroid, and the anaplastic cancer, which has the poorest prognosis (1, 2).Several common oncogenes, such as RAS, RET, BRAF and p53, have been involved in thyroid carcinogenesis (3). However, these are rarely used as prognostic factors in everyday clinical practice, since their frequency varies depending on the population while they mainly reflect the different genetic and environmental factors that induce carcinogenesis (1). On the other hand, insulin-like growth factor-I (IGF-I) regulates various aspects of cancer biology, such as cell proliferation, survival, differentiation and migration (4-7) and, thus, it has been implicated in the pathophysiol...

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confidence: 99%

IGF-IEc Expression Is Associated With Advanced Differentiated Thyroid Cancer

et al. 2019

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“…In the case of BC, the expression and biological role of IGF1 isoforms (mRNAs, proteins) was only studied in in vitro models [ 16 , 106 , 167 , 168 , 169 , 170 ].…”

Section: Igf1 Gene Alternative Splicing and Carcinogenesismentioning

confidence: 99%

“…Other study showed that the application of synthetic human Ec (hEc) peptide stimulated proliferation of MCF7 cells, but not hormone-resistant MDA-MB-231 cells. The MCF7 cells with stable expression of hEc have a greater proliferation and migratory capacity in comparison with mock or wt-type cells, as well as enhanced activity of the intracellular ERK1/2 pathway [ 170 ].…”

Section: Igf1 Gene Alternative Splicing and Carcinogenesismentioning

confidence: 99%

“…Pro-proliferative and anti-apoptotic properties, migration and invasion promotion, as well as EMT, angiogenesis, and metastasis induction mostly concern the IGF1Ec (MGF) isoform, both as the human Ec peptide [ 14 , 18 , 108 , 166 , 170 ] and IGF1Ec pro-forms [ 16 ]. These effects have been proved in hormone-sensitive breast cancer [ 16 , 170 ], prostate cancer [ 18 , 30 , 108 , 166 ], and osteosarcoma cells [ 14 , 15 ]. In prostate cancer cells, hEc exerts progression but not competence growth factor action, activating ERK1/2 without Akt phosphorylation [ 18 , 108 ].…”

Section: Aberrant Igf1 Isoform Expression (Mrnas Proteins) and Camentioning

confidence: 99%

“…Synthetic MGF (Ec peptide) exhibited mitogenic activity through mechanisms independent of IGF1R, INSR, and hybrid IGF1R/INSR in PC [ 108 ] and KLE cells [ 107 ]. Furthermore, in BC cells, hEc also enhances the intracellular ERK1/2 pathway [ 170 ], while osteosarcoma cell growth was stimulated via hEc peptide in an IGF1R/INSR-independent manner [ 14 ]. Moreover, an increase in cell cycle proteins (cyclin D) expression, enhanced cell migration, as well as pro-angiogenic and anti-apoptotic effects were noted, as compared to control group [ 15 ].…”

Section: Aberrant Igf1 Isoform Expression (Mrnas Proteins) and Camentioning

confidence: 99%

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Role of Alternatively Spliced Messenger RNA (mRNA) Isoforms of the Insulin-Like Growth Factor 1 (IGF1) in Selected Human Tumors

Kasprzak

Szaflarski

2020

IJMS

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Insulin-like growth factor 1 (IGF1) is a key regulator of tissue growth and development that is also implicated in the initiation and progression of various cancers. The human IGF1 gene contains six exons and five long introns, the transcription of which is controlled by two promoters (P1 and P2). Alternate promoter usage, as well as alternative splicing (AS) of IGF1, results in the expression of six various variants (isoforms) of mRNA, i.e., IA, IB, IC, IIA, IIB, and IIC. A mature 70-kDa IGF1 protein is coded only by exons 3 and 4, while exons 5 and 6 are alternatively spliced code for the three C-terminal E peptides: Ea (exon 6), Eb (exon 5), and Ec (fragments of exons 5 and 6). The most abundant of those transcripts is IGF1Ea, followed by IGF1Eb and IGF1Ec (also known as mechano-growth factor, MGF). The presence of different IGF1 transcripts suggests tissue-specific auto- and/or paracrine action, as well as separate regulation of both of these gene promoters. In physiology, the role of different IGF1 mRNA isoforms and pro-peptides is best recognized in skeletal muscle tissue. Their functions include the development and regeneration of muscles, as well as maintenance of proper muscle mass. In turn, in nervous tissue, a neuroprotective function of short peptides, produced as a result of IGF1 expression and characterized by significant blood-brain barrier penetrance, has been described and could be a potential therapeutic target. When it comes to the regulation of carcinogenesis, the potential biological role of different var iants of IGF1 mRNAs and pro-peptides is also intensively studied. This review highlights the role of IGF1 isoform expression (mRNAs, proteins) in physiology and different types of human tumors (e.g., breast cancer, cervical cancer, colorectal cancer, osteosarcoma, prostate and thyroid cancers), as well as mechanisms of IGF1 spliced variants involvement in tumor biology.

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Expression of IGF-IEc Isoform in Renal Cell Carcinoma Tissues

et al. 2020

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Background/Aim: Insulin-like growth factor-I (IGF-I) regulates various aspects of cancer biology. There is a growing body of evidence regarding the potential distinct role of IGF-I isoforms, particularly of IGF-IEc, in the pathophysiology of various human cancer types, however, there are no studies which examined the expression of the different IGF-I isoforms in renal cell carcinoma (RCC). This study aimed to characterize the expression of IGF-IEc in human RCC tissues and investigated whether its expression is associated with the histopathological type of RCC as well as with the overall survival of patients. Materials and Methods: Formalin-fixed paraffin-embedded renal tissue samples from 94 patients (58 males and 36 females) were assessed for IGF-IEc expression by immunohistochemistry. Results: RCC tissues showed mainly cytoplasmic IGF-IEc staining but immunoreactivity of IGF-IEc was also localized in the cell membrane. Significantly lower IGF-IEc expression was found in clear cell RCC vs. all other histological types (p=0.010), and this remained significant after adjusting for tumor size, grade, stage, and mitotic index (p<0.05) . No association was found between IGF-IEc expression level and overall survival of patients with RCC. Conclusion: The differential expression of IGF-IEc isoform among the RCC histopathological types may indicate its histological typespecific regulation and possibly suggests a discrete biological role of this isoform in the pathophysiology of RCC.Renal cell carcinoma (RCC) is the most common kidney malignancy, affecting men more than women, and metastatic disease at presentation occurs in up to one-third of patients. The pathological stage (size of the tumor and the extent of invasion), grade, and histological cell type are widely used in clinical practice for the prognosis of RCC (1). In particular, clear cell is the most common histological type of RCC accounting for 60-70% of cases (2). It represents a genetically and histologically diverse group of cancers that includes chromophobe, papillary, unclassified RCC, and other rare subtypes such as renal medullary carcinoma (3-6).Insulin-like growth factor-I (IGF-I) plays an important role in various aspects of cancer biology, such as cell growth, apoptosis resistance, cell differentiation and migration (7-10) and, thus, it has been implicated in the pathophysiology and prognosis of several human cancer types (11-14), including RCC (2,15,16). IGF-I is not only secreted by the liver, but is also produced by other organs such as skeletal muscle, kidney and brain (17-27). The IGF1 gene consists of six exons and can produce multiple heterogeneous transcripts via alternative splicing during its transcription, namely IGF-IEa, IGF-IEb, and IGF-IEc, which encode the corresponding IGF-I protein isoforms (24,26). Mature IGF-I peptide represents the common bioactive product of all IGF-I isoforms (24, 28) and numerous studies have shown that this peptide is involved in cell survival and protection from apoptosis, as well as in the process of uncontro...

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The COOH-terminus of the IGF-1Ec Isoform Enhances the Proliferation and Migration of Human MCF-7 Breast Cancer Cells

Abstract: hEc stimulates the proliferation and migration of MCF-7 breast cancer cells and enhances the intracellular ERK1/2 signaling.

Cited by 3 publications

References 31 publications

IGF-IEc Expression Is Associated With Advanced Differentiated Thyroid Cancer

IGF-IEc Expression Is Associated With Advanced Differentiated Thyroid Cancer

Role of Alternatively Spliced Messenger RNA (mRNA) Isoforms of the Insulin-Like Growth Factor 1 (IGF1) in Selected Human Tumors

Expression of IGF-IEc Isoform in Renal Cell Carcinoma Tissues

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