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Erschienen in: Archives of Gynecology and Obstetrics 1/2015

01.07.2015 | Gynecologic Endocrinology and Reproductive Medicine

K-Ras 4A Transcript variant is up-regulated in eutopic endometrium of endometriosis patients during proliferative phase of menstrual cycle

verfasst von: Maryam Shahrabi-Farahani, Shirin Shahbazi, Reza Mahdian, Soheila Amini-Moghaddam

Erschienen in: Archives of Gynecology and Obstetrics | Ausgabe 1/2015

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Abstract

Aims

K-Ras transcripts comprise two main isoforms: K-Ras 4A and K-Ras 4B, which act differently. The expression of both isoforms was reported in many human tissues. However, K-Ras 4B was the major expressed transcript variant. An increased expression of K-Ras 4B mRNA was reported in eutopic endometrium of endometriosis patients. In this way, we aimed to study the expression of K-Ras 4A transcript in eutopic endometrium related to endometriosis.

Methods

Employing exon4-flanking primers, K-Ras isoforms were simultaneously amplified in a RT-PCR reaction. Quantitative real-time PCR was performed using GAPDH as an internal control. K-Ras 4A transcript expression in eutopic endometrium was analyzed by ΔΔC T method.

Results

We identified existence of both of K-Ras 4A and K-Ras 4B in eutopic endometrium of patients and controls. Quantitative real-time analysis demonstrated that K-Ras 4A expression was 2.7-fold higher in endometriosis than non-endometriosis eutopic samples. Interestingly, this overexpression mainly occurs through the proliferative phase of menstrual cycle.

Conclusion

The findings bring to light the eminent role of K-Ras 4A in endometriosis. This splice variant which is known for promoting apoptosis could be an effective factor in balance between proliferation and death of eutopic endometrial cells.
Literatur
1.
Zurück zum Zitat Rogers PA, D’Hooghe TM, Fazleabas A, Giudice LC, Montgomery GW, Petraglia F, Taylor RN (2013) Defining future directions for endometriosis research: workshop report from the 2011 World Congress of Endometriosis in Montpellier. France Reprod Sci 20(5):483–499CrossRef Rogers PA, D’Hooghe TM, Fazleabas A, Giudice LC, Montgomery GW, Petraglia F, Taylor RN (2013) Defining future directions for endometriosis research: workshop report from the 2011 World Congress of Endometriosis in Montpellier. France Reprod Sci 20(5):483–499CrossRef
2.
Zurück zum Zitat Haas D, Chvatal R, Reichert B, Renner S, Shebl O, Binder H, Wurm P, Oppelt P (2012) Endometriosis: a premenopausal disease? Age pattern in 42,079 patients with endometriosis. Arch Gynecol Obstet 286(3):667–670CrossRefPubMed Haas D, Chvatal R, Reichert B, Renner S, Shebl O, Binder H, Wurm P, Oppelt P (2012) Endometriosis: a premenopausal disease? Age pattern in 42,079 patients with endometriosis. Arch Gynecol Obstet 286(3):667–670CrossRefPubMed
3.
Zurück zum Zitat Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC (2007) Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 148(8):3814–3826CrossRefPubMed Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC (2007) Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 148(8):3814–3826CrossRefPubMed
4.
Zurück zum Zitat Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T (2005) Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 11(1):63–70CrossRefPubMed Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T (2005) Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 11(1):63–70CrossRefPubMed
5.
Zurück zum Zitat Vercellini P, Trecca D, Oldani S, Fracchiolla NS, Neri A, Crosignani PG (1994) Analysis of p53 and ras gene mutations in endometriosis. Gynecol Obstet Invest 38(1):70–71CrossRefPubMed Vercellini P, Trecca D, Oldani S, Fracchiolla NS, Neri A, Crosignani PG (1994) Analysis of p53 and ras gene mutations in endometriosis. Gynecol Obstet Invest 38(1):70–71CrossRefPubMed
6.
Zurück zum Zitat Otsuka J, Okuda T, Sekizawa A, Amemiya S, Saito H, Okai T, Kushima M, Tachikawa T (2004) K-ras mutation may promote carcinogenesis of endometriosis leading to ovarian clear cell carcinoma. Med Electron Microsc 37(3):188–192CrossRefPubMed Otsuka J, Okuda T, Sekizawa A, Amemiya S, Saito H, Okai T, Kushima M, Tachikawa T (2004) K-ras mutation may promote carcinogenesis of endometriosis leading to ovarian clear cell carcinoma. Med Electron Microsc 37(3):188–192CrossRefPubMed
7.
Zurück zum Zitat Kalnina Z, Zayakin P, Silina K, Line A (2005) Alterations of pre-mRNA splicing in cancer. Genes Chromosomes Cancer 42(4):342–357CrossRefPubMed Kalnina Z, Zayakin P, Silina K, Line A (2005) Alterations of pre-mRNA splicing in cancer. Genes Chromosomes Cancer 42(4):342–357CrossRefPubMed
8.
Zurück zum Zitat Plowman SJ, Berry RL, Bader SA, Luo F, Arends MJ, Harrison DJ, Hooper ML, Patek CE (2006) K-ras 4A and 4B are co-expressed widely in human tissues, and their ratio is altered in sporadic colorectal cancer. J Exp Clin Cancer Res 25(2):259–267PubMed Plowman SJ, Berry RL, Bader SA, Luo F, Arends MJ, Harrison DJ, Hooper ML, Patek CE (2006) K-ras 4A and 4B are co-expressed widely in human tissues, and their ratio is altered in sporadic colorectal cancer. J Exp Clin Cancer Res 25(2):259–267PubMed
9.
Zurück zum Zitat Hancock JF (2003) Ras proteins: different signals from different locations. Nat Rev Mol Cell Biol 4(5):373–384CrossRefPubMed Hancock JF (2003) Ras proteins: different signals from different locations. Nat Rev Mol Cell Biol 4(5):373–384CrossRefPubMed
10.
Zurück zum Zitat Plowman SJ, Williamson DJ, O’Sullivan MJ, Doig J, Ritchie AM, Harrison DJ, Melton DW, Arends MJ, Hooper ML, Patek CE (2003) While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable. Mol Cell Biol 23(24):9245–9250CrossRefPubMedCentralPubMed Plowman SJ, Williamson DJ, O’Sullivan MJ, Doig J, Ritchie AM, Harrison DJ, Melton DW, Arends MJ, Hooper ML, Patek CE (2003) While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable. Mol Cell Biol 23(24):9245–9250CrossRefPubMedCentralPubMed
11.
Zurück zum Zitat Voice JK, Klemke RL, Le A, Jackson JH (1999) Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J Biol Chem 274(24):17164–17170CrossRefPubMed Voice JK, Klemke RL, Le A, Jackson JH (1999) Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J Biol Chem 274(24):17164–17170CrossRefPubMed
12.
Zurück zum Zitat Grechukhina O, Petracco R, Popkhadze S, Massasa E, Paranjape T, Chan E, Flores I, Weidhaas JB, Taylor HS (2012) A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO Mol Med 4(3):206–217CrossRefPubMedCentralPubMed Grechukhina O, Petracco R, Popkhadze S, Massasa E, Paranjape T, Chan E, Flores I, Weidhaas JB, Taylor HS (2012) A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO Mol Med 4(3):206–217CrossRefPubMedCentralPubMed
13.
Zurück zum Zitat Laudanski P, Szamatowicz J, Kowalczuk O, Kuzmicki M, Grabowicz M, Chyczewski L (2009) Expression of selected tumor suppressor and oncogenes in endometrium of women with endometriosis. Hum Reprod 24(8):1880–1890CrossRefPubMed Laudanski P, Szamatowicz J, Kowalczuk O, Kuzmicki M, Grabowicz M, Chyczewski L (2009) Expression of selected tumor suppressor and oncogenes in endometrium of women with endometriosis. Hum Reprod 24(8):1880–1890CrossRefPubMed
14.
Zurück zum Zitat Farahani MS, Shahbazi S, Moghaddam SA, Mahdian R(2014) Evaluation of KRAS gene expression and LCS6 variant in genomic and cell-free DNA of Iranian women with endometriosis. Reprod Sci Farahani MS, Shahbazi S, Moghaddam SA, Mahdian R(2014) Evaluation of KRAS gene expression and LCS6 variant in genomic and cell-free DNA of Iranian women with endometriosis. Reprod Sci
15.
Zurück zum Zitat Wang Y, You M (2001) Alternative splicing of the K-ras gene in mouse tissues and cell lines. Exp Lung Res 27(3):255–267CrossRefPubMed Wang Y, You M (2001) Alternative splicing of the K-ras gene in mouse tissues and cell lines. Exp Lung Res 27(3):255–267CrossRefPubMed
16.
Zurück zum Zitat Koera K, Nakamura K, Nakao K, Miyoshi J, Toyoshima K, Hatta T, Otani H, Aiba A, Katsuki M (1997) K-ras is essential for the development of the mouse embryo. Oncogene 15(10):1151–1159CrossRefPubMed Koera K, Nakamura K, Nakao K, Miyoshi J, Toyoshima K, Hatta T, Otani H, Aiba A, Katsuki M (1997) K-ras is essential for the development of the mouse embryo. Oncogene 15(10):1151–1159CrossRefPubMed
17.
Zurück zum Zitat Johnson L, Greenbaum D, Cichowski K, Mercer K, Murphy E, Schmitt E, Bronson RT, Umanoff H, Edelmann W, Kucherlapati R et al (1997) K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev 11(19):2468–2481CrossRefPubMedCentralPubMed Johnson L, Greenbaum D, Cichowski K, Mercer K, Murphy E, Schmitt E, Bronson RT, Umanoff H, Edelmann W, Kucherlapati R et al (1997) K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev 11(19):2468–2481CrossRefPubMedCentralPubMed
18.
Zurück zum Zitat Hurst BS, Shimp KE, Elliot M, Marshburn PB, Parsons J, Bahrani-Mostafavi Z (2014) Molecular evaluation of proliferative-phase endometrium may provide insight about the underlying causes of infertility in women with endometriosis. Arch Gynecol Obstet 289(5):1119–1124CrossRefPubMed Hurst BS, Shimp KE, Elliot M, Marshburn PB, Parsons J, Bahrani-Mostafavi Z (2014) Molecular evaluation of proliferative-phase endometrium may provide insight about the underlying causes of infertility in women with endometriosis. Arch Gynecol Obstet 289(5):1119–1124CrossRefPubMed
19.
Zurück zum Zitat Critchley HO, Saunders PT (2009) Hormone receptor dynamics in a receptive human endometrium. Reprod Sci 16(2):191–199CrossRefPubMed Critchley HO, Saunders PT (2009) Hormone receptor dynamics in a receptive human endometrium. Reprod Sci 16(2):191–199CrossRefPubMed
21.
Zurück zum Zitat Plowman SJ, Arends MJ, Brownstein DG, Luo F, Devenney PS, Rose L, Ritchie AM, Berry RL, Harrison DJ, Hooper ML et al (2006) The K-Ras 4A isoform promotes apoptosis but does not affect either lifespan or spontaneous tumor incidence in aging mice. Exp Cell Res 312(1):16–26CrossRefPubMed Plowman SJ, Arends MJ, Brownstein DG, Luo F, Devenney PS, Rose L, Ritchie AM, Berry RL, Harrison DJ, Hooper ML et al (2006) The K-Ras 4A isoform promotes apoptosis but does not affect either lifespan or spontaneous tumor incidence in aging mice. Exp Cell Res 312(1):16–26CrossRefPubMed
22.
Zurück zum Zitat Vaskivuo TE, Stenback F, Karhumaa P, Risteli J, Dunkel L, Tapanainen JS (2000) Apoptosis and apoptosis-related proteins in human endometrium. Mol Cell Endocrinol 165(1–2):75–83CrossRefPubMed Vaskivuo TE, Stenback F, Karhumaa P, Risteli J, Dunkel L, Tapanainen JS (2000) Apoptosis and apoptosis-related proteins in human endometrium. Mol Cell Endocrinol 165(1–2):75–83CrossRefPubMed
23.
Zurück zum Zitat Kokawa K, Shikone T, Nakano R (1996) Apoptosis in the human uterine endometrium during the menstrual cycle. J Clin Endocrinol Metab 81(11):4144–4147PubMed Kokawa K, Shikone T, Nakano R (1996) Apoptosis in the human uterine endometrium during the menstrual cycle. J Clin Endocrinol Metab 81(11):4144–4147PubMed
24.
Zurück zum Zitat Dmowski WP, Ding J, Shen J, Rana N, Fernandez BB, Braun DP (2001) Apoptosis in endometrial glandular and stromal cells in women with and without endometriosis. Hum Reprod 16(9):1802–1808CrossRefPubMed Dmowski WP, Ding J, Shen J, Rana N, Fernandez BB, Braun DP (2001) Apoptosis in endometrial glandular and stromal cells in women with and without endometriosis. Hum Reprod 16(9):1802–1808CrossRefPubMed
Metadaten
Titel
K-Ras 4A Transcript variant is up-regulated in eutopic endometrium of endometriosis patients during proliferative phase of menstrual cycle
verfasst von
Maryam Shahrabi-Farahani
Shirin Shahbazi
Reza Mahdian
Soheila Amini-Moghaddam
Publikationsdatum
01.07.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
Archives of Gynecology and Obstetrics / Ausgabe 1/2015
Print ISSN: 0932-0067
Elektronische ISSN: 1432-0711
DOI
https://doi.org/10.1007/s00404-014-3596-7

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