Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 12/2014

01-12-2014 | Research Article

RKIP inhibits gastric cancer cell survival and invasion by regulating the expression of HMGA2 and OPN

Authors: Hongyi Liu, Peng Li, Bing Li, Peng Sun, Jiajin Zhang, Baishi Wang, Baoqing Jia

Published in: Tumor Biology | Issue 12/2014

Login to get access

Abstract

The objective of this study was to explore the mechanism via which Raf kinase inhibitor protein (RKIP) suppresses the invasion of gastric cancer cells and promote apoptosis, with an attempt to provide evidences for the application of RKIP in treating gastric cancer. The recombinant plasmid pcDNA3.1-RKIP or RKIP-shRNA was transfected into the gastric cancer cell line SGC-7901 using liposome. Then, the messenger RNA (mRNA) and protein expressions of RKIP, HMGA2, and OPN were detected using qPCR and Western blotting. The effects of HMGA2 on the proliferation, apoptosis, and invasion of SGC-7901 cells were detected using flow cytometry and Transwell assay. To further explore the regulatory effect of PKIP on the biological activities of HMGA2, we over-expressed or knock down RKIP and HMGA2 simultaneously and detected its effects on the proliferation, apoptosis, and invasion of SGC-7901 cells. As shown by qPCR and Western blotting, after over-expression of RKIP in SGC-7901 cells, the mRNA and protein expressions of RKIP significantly increased (P < 0.01), whereas the mRNA and protein expressions of HMGA2 and OPN significantly decreased (P < 0.01). In contrast, the transfection of RKIP-shRNA in the SGC-7901 cells resulted in opposite results. After over-expression of HMGA2 in SGC-7901 cells, the protein expression of HMGA2 significantly increased (P < 0.01); however, it significantly decreased after the transfection of HMGA2-shRNA (P < 0.01). As shown by Transwell assay and flow cytometry, After the over-expression of HMGA2 in SGC-7901 cells, the (G2 + S) phase fraction significantly increased (P < 0.01); also, the percentage of the apoptotic cells significantly declined (P < 0.05) and the number of invasive cells significantly increased (P < 0.05). However, the interference of the expression of HMGA2 resulted in opposite results. The simultaneous over-expression of RKIP and HMGA2 in SGC-7901 cells or the simultaneous interference of RKIP and HMGA2 showed no significant difference with the control group in terms of (G2 + S) phase fraction, percentage of apoptotic cells, and number of invasive cells (P > 0.05). In conclusion, RKIP can inhibit the survival and invasion of gastric cancer cells and promote apoptosis, possibly by regulating the expression of HMGA2 or OPN.
Literature
1.
Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, et al. Suppression of raf-1 kinase activity and map kinase signalling by rkip. Nature. 1999;401:173–7.PubMedCrossRef
2.
Zeng L, Imamoto A, Rosner MR. Raf kinase inhibitory protein (rkip): a physiological regulator and future therapeutic target. Expert Opin Ther Targets. 2008;12:1275–87.PubMedCrossRef
3.
Lu TP, Tsai MH, Hsiao CK, Lai LC, Chuang EY. Expression and functions of semaphorins in cancer. Transl Cancer Res. 2012;1:74–87.
4.
Khamis ZI, Iczkowski KA, Sang QX. Metastasis suppressors in human benign prostate, intraepithelial neoplasia, and invasive cancer: their prospects as therapeutic agents. Med Res Rev. 2012;32:1026–77.PubMedCrossRef
5.
Yamada Y. Molecular therapy for gastric cancer. Chin Clin Oncol. 2013;2:5.PubMed
6.
Wang YX, Wang DW, Zhu XM, Zhao F, Leung KC. Carbon coated superparamagnetic iron oxide nanoparticles for sentinel lymph nodes mapping. Quant Imaging Med Surg. 2012;2:53–6.PubMedPubMedCentral
7.
8.
Smith HS, Smith JM, Smith AR. An overview of nausea/vomiting in palliative medicine. Ann Palliat Med. 2012;1:103–14.PubMed
9.
Fedele M, Palmieri D, Fusco A. Hmga2: a pituitary tumour subtype-specific oncogene? Mol Cell Endocrinol. 2010;326:19–24.PubMedCrossRef
10.
11.
Cleynen I, Van de Ven WJ. The hmga proteins: a myriad of functions (review). Int J Oncol. 2008;32:289–305.PubMed
12.
13.
Jonson L, Christiansen J, Hansen TV, Vikesa J, Yamamoto Y, Nielsen FC. Imp3 rnp safe houses prevent mirna-directed hmga2 mrna decay in cancer and development. Cell Rep. 2014;7:539–51.PubMedCrossRef
14.
Watanabe S, Ueda Y, Akaboshi S, Hino Y, Sekita Y, Nakao M. Hmga2 maintains oncogenic ras-induced epithelial-mesenchymal transition in human pancreatic cancer cells. Am J Pathol. 2009;174:854–68.PubMedPubMedCentralCrossRef
15.
Pagel CN, Wasgewatte Wijesinghe DK, Taghavi Esfandouni N, Mackie EJ. Osteopontin, inflammation and myogenesis: influencing regeneration, fibrosis and size of skeletal muscle. J Cell Commun Signal. 2013.
16.
Nagoshi S. Osteopontin: versatile modulator of liver diseases. Hepatol Res Off J Jpn Soc Hepatol. 2014;44:22–30.CrossRef
17.
Gimba ER, Tilli TM. Human osteopontin splicing isoforms: known roles, potential clinical applications and activated signaling pathways. Cancer Lett. 2013;331:11–7.PubMedCrossRef
18.
Cheng C, Gao S, Lei G. Association of osteopontin with osteoarthritis. Rheumatol Int. 2014.
19.
Chien CY, Tsai HT, Su LJ, Chuang HC, Shiu LY, Huang CC, et al. Aurora-a signaling is activated in advanced stage of squamous cell carcinoma of head and neck cancer and requires osteopontin to stimulate invasive behavior. Oncotarget. 2014;5:2243–62.PubMedPubMedCentralCrossRef
20.
Hunter GK. Role of osteopontin in modulation of hydroxyapatite formation. Calcif Tissue Int. 2013;93:348–54.PubMedCrossRef
21.
Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z, et al. Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst. 2003;95:878–89.PubMedCrossRef
22.
Xu YF, Yi Y, Qiu SJ, Gao Q, Li YW, Dai CX, et al. Pebp1 downregulation is associated to poor prognosis in hcc related to hepatitis b infection. J Hepatol. 2010;53:872–9.PubMedCrossRef
23.
Lin K, Baritaki S, Militello L, Malaponte G, Bevelacqua Y, Bonavida B. The role of b-raf mutations in melanoma and the induction of emt via dysregulation of the nf-kappab/snail/rkip/pten circuit. Genes Cancer. 2010;1:409–20.PubMedPubMedCentralCrossRef
24.
Al-Mulla F, Hagan S, Al-Ali W, Jacob SP, Behbehani AI, Bitar MS, et al. Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability. J Clin Pathol. 2008;61:524–9.PubMedCrossRef
25.
Li HZ, Gao Y, Zhao XL, Liu YX, Sun BC, Yang J, et al. Effects of raf kinase inhibitor protein expression on metastasis and progression of human breast cancer. Mol Cancer Res. 2009;7:832–40.PubMedCrossRef
26.
Minn AJ, Bevilacqua E, Yun J, Rosner MR. Identification of novel metastasis suppressor signaling pathways for breast cancer. Cell Cycle. 2012;11:2452–7.PubMedPubMedCentralCrossRef
27.
Bonavida B, Baritaki S. The novel role of yin yang 1 in the regulation of epithelial to mesenchymal transition in cancer via the dysregulated nf-kappab/snail/yy1/rkip/pten circuitry. Crit Rev Oncog. 2011;16:211–26.PubMedCrossRef
28.
Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: classification, histology and application of molecular pathology. J Gastrointest Oncol. 2012;3:251–61.PubMedPubMedCentral
29.
Wu Z, Fu C, Shi L, Ruan L, Lin D, Guo C. Structural basis for rkip binding with its substrate raf1 kinase. Biotechnol Lett. 2014;36:1869–74.PubMedCrossRef
30.
Bu Z, Zheng Z, Zhang L, Li Z, Sun Y, Dong B, et al. LGR5 is a promising biomarker for patients with stage I and II gastric cancer. Chin J Cancer Res. 2013;25:79–89.PubMedPubMedCentral
31.
McDaniel K, Correa R, Zhou T, Johnson C, Francis H, Glaser S, et al. Functional role of microvesicles in gastrointestinal malignancies. Ann Transl Med. 2013;1:4.PubMedPubMedCentral
32.
Franceschi F, Zuccala G, Roccarina D, Gasbarrini A. Clinical effects of helicobacter pylori outside the stomach. Nat Rev Gastroenterol Hepatol. 2014;11:234–42.PubMedCrossRef
33.
Bu Z, Ji J. A current view of gastric cancer in China. Transl Gastrointest Cancer. 2013;2(S1):1–4.
34.
Sun YF, Yang XR, Zhou J, Qiu SJ, Fan J, Xu Y. Circulating tumor cells: advances in detection methods, biological issues, and clinical relevance. J Cancer Res Clin Oncol. 2011;137:1151–73.PubMedCrossRef
35.
Merchionne F, Iacopino P, Minoia C, Iacobazzi A, Rana A, Serratl S, et al. Targeted strategies in the treatment of primary gastric lymphomas: from rituximab to recent insights into potential new drugs. Curr Med Chem. 2014;21:1005–16.PubMedCrossRef
36.
Hardbower DM, Peek Jr RM, Wilson KT. At the bench: helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer. J Leukoc Biol. 2014;96:201–12.PubMedPubMedCentralCrossRef
37.
Yang W, Raufi A, Klempner SJ. Targeted therapy for gastric cancer: molecular pathways and ongoing investigations. Biochim Biophys Acta. 1846;2014:232–7.
38.
Al-Mulla F, Bitar MS, Taqi Z, Yeung KC. Rkip: much more than raf kinase inhibitory protein. J Cell Physiol. 2013;228:1688–702.PubMedCrossRef
39.
Escara-Wilke J, Yeung K, Keller ET. Raf kinase inhibitor protein (rkip) in cancer. Cancer Metastasis Rev. 2012;31:615–20.PubMedCrossRef
40.
Zhou H, Guo W, Zhao Y, Wang Y, Zha R, Ding J, et al. Microrna-26a acts as a tumor suppressor inhibiting gallbladder cancer cell proliferation by directly targeting hmga2. Int J Oncol. 2014;44:2050–8.PubMedCrossRef
41.
Xi YN, Xin XY, Ye HM. Effects of hmga2 on malignant degree, invasion, metastasis, proliferation and cellular morphology of ovarian cancer cells. Asian Pac J Trop Med. 2014;7:289–92.PubMedCrossRef
42.
Dangi-Garimella S, Yun J, Eves EM, Newman M, Erkeland SJ, Hammond SM, et al. Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving lin28 and let-7. EMBO J. 2009;28:347–58.PubMedPubMedCentralCrossRef
43.
Wei J, Li H, Wang S, Li T, Fan J, Liang X, et al. Let-7 enhances osteogenesis and bone formation while repressing adipogenesis of human stromal/mesenchymal stem cells by regulating hmga2. Stem Cells Dev. 2014;23:1452–63.PubMedPubMedCentralCrossRef
44.
Chen KJ, Hou Y, Wang K, Li J, Xia Y, Yang XY, et al. Reexpression of let-7 g microrna inhibits the proliferation and migration via k-ras/hmga2/snail axis in hepatocellular carcinoma. BioMed Res Int. 2014;2014:742417.PubMedPubMedCentral
45.
Sun M, Gomes S, Chen P, Frankenberger CA, Sankarasharma D, Chung CH, et al. Rkip and hmga2 regulate breast tumor survival and metastasis through lysyl oxidase and syndecan-2. Oncogene. 2013;33:3528–37.PubMedPubMedCentralCrossRef
Metadata
Title
RKIP inhibits gastric cancer cell survival and invasion by regulating the expression of HMGA2 and OPN
Authors
Hongyi Liu
Peng Li
Bing Li
Peng Sun
Jiajin Zhang
Baishi Wang
Baoqing Jia
Publication date
01-12-2014
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-2486-8

Other articles of this Issue 12/2014

Tumor Biology 12/2014 Go to the issue

Research Article

Zebrafish xenotransplantation model for cancer stem-like cell study and high-throughput screening of inhibitors

Research Article

Overcoming 5-Fu resistance in human non-small cell lung cancer cells by the combination of 5-Fu and cisplatin through the inhibition of glucose metabolism

Research Article

MiR-25 promotes ovarian cancer proliferation and motility by targeting LATS2

Research Article

A triterpenoid saponin from Adenophora triphylla var. japonica suppresses the growth of human gastric cancer cells via regulation of apoptosis and autophagy

Research Article

Contribution of cyclin D1 (CCND1) and E-cadherin (CDH1) alterations to colorectal cancer susceptibility: a case–control study

Research Article

Circulating miR-148a is a significant diagnostic and prognostic biomarker for patients with osteosarcoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits