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
Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

DC - SIGNR by influencing the lncRNA HNRNPKP2 upregulates the expression of CXCR4 in gastric cancer liver metastasis

Authors: Yu Zhang, Qianshi Zhang, Mengyang Zhang, Menglang Yuan, Zhaohui Wang, Jingbo Zhang, Xu Zhou, Yinan Zhang, Fang Lin, Heya NA, Shuangyi Ren, Yunfei Zuo

Published in: Molecular Cancer | Issue 1/2017

Login to get access

Abstract

Background

Profiling evidences of selectin demonstrate that they play an crucial role in cancer progression and metastasis. However, DC-SIGNR as a family member of selectin participates in gastric cancer liver metastasis remains unknown.

Methods

The serum level of DC-SIGNR was evaluated in gastric cancer patients by ELISA. Manipulation DC-SIGNR expression in BGC823 and SGC7901 cell lines was mediated by lentivirus. Investigation the biological effects of DC-SIGNR were verified by MTT, wounding and transwell in vitro and experiments on animals to confirm gastric cancer liver metastasis by IVIS. Insights of the mechanism were employed microarray and bioinformatic analysis. Further to confirm the results were conducted by qRT-PCR, western blot and by flow cytometry.

Results

DC-SIGNR serum level was significantly increased in gastric cancer patients compared with healthy group. Additionally, DC-SIGNR level was associated with an advanced pathological stage in gastric cancer patients. DC-SIGNR knockdown inhibited the proliferation, migration and invasion of gastric cancer cells in vitro and suppressed the liver metastasis in vivo. While, DC-SIGNR overexpression promoted cell proliferation, migration and invasion. In mechanism, HNRNPKP2 as a lncRNA was upregulated after DC-SIGNR knockdown. Importantly, STAT5A promoted HNRNPKP2 expression after knockdown DC-SIGNR. Furthermore after HNRNPKP2 depletion, the downstream target gene CXCR4 was downregulated.

Conclusions

DC-SIGNR promoted gastric cancer liver metastasis mediated with HNRNPKP2 which expression was regulated by STAT5A. And HNRNPKP2 decreased the expression of downstream target gene CXCR4. These findings indicated potential therapeutic candidates for gastric cancer liver metastasis.
Appendix
Available only for authorised users
Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMed
2.
Ferro A, Peleteiro B, Malvezzi M, et al. Worldwide trends in gastric cancer mortality (1980–2011), with predictions to 2015, and incidence by subtype. Eur J Cancer. 2014;50:1330–44.CrossRefPubMed
3.
Sakamoto Y, Ohyama S, Yamamoto J, et al. Surgical resection of liver metastases of gastric cancer: an analysis of a 17-year experience with 22 patients. Surgery. 2003;133:507–11.CrossRefPubMed
4.
Koga R, Yamamoto J, Ohyama S, et al. Liver resection for metastatic gastric cancer: experience with 42 patients including eight long-term survivors. Jpn J Clin Oncol. 2007;37:836–42.CrossRefPubMed
5.
Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725–30.CrossRefPubMed
6.
Kakeji Y, Morita M, Maehara Y. Strategies for treating liver metastasis from gastric cancer. Surg Today. 2010;40:287–94.CrossRefPubMed
7.
Witz IP. The selectin-selectin ligand axis in tumor progression. Cancer Metastasis Rev. 2008;27:19–30.CrossRefPubMed
8.
Zuo Y, Ren S, Wang M, et al. Novel roles of liver sinusoidal endothelial cell lectin in colon carcinoma cell adhesion, migration and in-vivo metastasis to the liver. Gut. 2013;62:1169–78.CrossRefPubMed
9.
Benekli M, Gullu IH, Tekuzman G, et al. Circulating intercellular adhesion molecule-1 and E-selectin levels in gastric cancer. Br J Cancer. 1998;78:267–71.CrossRefPubMedPubMedCentral
10.
Khatib AM, Kontogiannea M, Fallavollita L, et al. Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Res. 1999;59:1356–61.PubMed
11.
Brodt P, Fallavollita L, Bresalier RS, et al. Liver endothelial E-selectin mediates carcinoma cell adhesion and promotes liver metastasis. Int J Cancer. 1997;71:612–9.CrossRefPubMed
12.
Khatib AM, Fallavollita L, Wancewicz EV, et al. Inhibition of hepatic endothelial E-selectin expression by C-raf antisense oligonucleotides blocks colorectal carcinoma liver metastasis. Cancer Res. 2002;62:5393–8.PubMed
13.
Jiang Y, Zhang C, Chen K, et al. The clinical significance of DC-SIGN and DC-SIGNR, which are novel markers expressed in human colon cancer. PLoS One. 2014;9:e114748.CrossRefPubMedPubMedCentral
14.
Zhao J, Liu Y, Huang G, et al. Long non-coding RNAs in gastric cancer: versatile mechanisms and potential for clinical translation. Am J Cancer Res. 2015;5:907–27.PubMedPubMedCentral
15.
Zhao Y, Guo Q, Chen J, et al. Role of long non-coding RNA HULC in cell proliferation, apoptosis and tumor metastasis of gastric cancer: a clinical and in vitro investigation. Oncol Rep. 2014;31:358–64.PubMed
16.
Xu TP, Huang MD, Xia R, et al. Decreased expression of the long non-coding RNA FENDRR is associated with poor prognosis in gastric cancer and FENDRR regulates gastric cancer cell metastasis by affecting fibronectin1 expression. J Hematol Oncol. 2014;7:63.CrossRefPubMedPubMedCentral
17.
Hu Y, Wang J, Qian J, et al. Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. Cancer Res. 2014;74:6890–902.CrossRefPubMed
18.
Liu XH, Sun M, Nie FQ, et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.CrossRefPubMedPubMedCentral
19.
20.
21.
Zhu BM, Kang K, Yu JH, et al. Genome-wide analyses reveal the extent of opportunistic STAT5 binding that does not yield transcriptional activation of neighboring genes. Nucleic Acids Res. 2012;40:4461–72.CrossRefPubMedPubMedCentral
22.
Sutton A, Friand V, Brule-Donneger S, et al. Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol Cancer Res. 2007;5:21–33.CrossRefPubMed
23.
Martinez-Nunez RT, Louafi F, Friedmann PS, et al. MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) by down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). J Biol Chem. 2009;284:16334–42.CrossRefPubMedPubMedCentral
24.
Tserel L, Runnel T, Kisand K, et al. MicroRNA expression profiles of human blood monocyte-derived dendritic cells and macrophages reveal miR-511 as putative positive regulator of Toll-like receptor 4. J Biol Chem. 2011;286:26487–95.CrossRefPubMedPubMedCentral
25.
Faghihi MA, Modarresi F, Khalil AM, et al. Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008;14:723–30.CrossRefPubMedPubMedCentral
26.
27.
Zhang B, Kirov S, Snoddy J. WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res. 2005;33:W741–748.CrossRefPubMedPubMedCentral
28.
Johnsson P, Ackley A, Vidarsdottir L, et al. A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. Nat Struct Mol Biol. 2013;20:440–6.CrossRefPubMedPubMedCentral
29.
Chung BM, Arutyunov A, Ilagan E, et al. Regulation of C-X-C chemokine gene expression by keratin 17 and hnRNP K in skin tumor keratinocytes. J Cell Biol. 2015;208:613–27.CrossRefPubMedPubMedCentral
30.
Michelotti EF, Michelotti GA, Aronsohn AI, et al. Heterogeneous nuclear ribonucleoprotein K is a transcription factor. Mol Cell Biol. 1996;16:2350–60.CrossRefPubMedPubMedCentral
31.
Ostareck-Lederer A, Ostareck DH, Cans C, et al. c-Src-mediated phosphorylation of hnRNP K drives translational activation of specifically silenced mRNAs. Molecular and cellular biology. 2002;22:4535–4543.
32.
Moumen A, Masterson P, O'Connor MJ, et al. hnRNP K: an HDM2 target and transcriptional coactivator of p53 in response to DNA damage. Cell. 2005;123:1065–78.CrossRefPubMed
33.
Enge M, Bao W, Hedstrom E, et al. MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53. Cancer Cell. 2009;15:171–83.CrossRefPubMed
34.
de Hoog CL, Foster LJ, Mann M. RNA and RNA binding proteins participate in early stages of cell spreading through spreading initiation centers. Cell. 2004;117:649–62.CrossRefPubMed
35.
Inoue A, Sawata SY, Taira K, et al. Loss-of-function screening by randomized intracellular antibodies: identification of hnRNP-K as a potential target for metastasis. Proc Natl Acad Sci U S A. 2007;104:8983–8.CrossRefPubMedPubMedCentral
36.
Wang P, Xue Y, Han Y, et al. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science. 2014;344:310–3.CrossRefPubMed
37.
Zhang EB, Kong R, Yin DD, et al. Long noncoding RNA ANRIL indicates a poor prognosis of gastric cancer and promotes tumor growth by epigenetically silencing of miR-99a/miR-449a. Oncotarget. 2014;5:2276–92.CrossRefPubMedPubMedCentral
38.
Hirata H, Hinoda Y, Shahryari V, et al. Long Noncoding RNA MALAT1 Promotes Aggressive Renal Cell Carcinoma through Ezh2 and Interacts with miR-205. Cancer Res. 2015;75:1322–31.CrossRefPubMed
39.
Yang F, Xue X, Bi J, et al. Long noncoding RNA CCAT1, which could be activated by c-Myc, promotes the progression of gastric carcinoma. J Cancer Res Clin Oncol. 2013;139:437–45.CrossRefPubMed
40.
Levine RL, Pardanani A, Tefferi A, et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673–83.CrossRefPubMed
41.
Silva M, Richard C, Benito A, et al. Expression of Bcl-x in erythroid precursors from patients with polycythemia vera. N Engl J Med. 1998;338:564–71.CrossRefPubMed
42.
Mathot L, Stenninger J. Behavior of seeds and soil in the mechanism of metastasis: a deeper understanding. Cancer Sci. 2012;103:626–31.CrossRefPubMed
43.
44.
Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol. 2004;14:171–9.CrossRefPubMed
45.
46.
Ehling J, Tacke F. Role of chemokine pathways in hepatobiliary cancer. Cancer Lett. 2016;379:173–83.CrossRefPubMed
Metadata
Title
DC - SIGNR by influencing the lncRNA HNRNPKP2 upregulates the expression of CXCR4 in gastric cancer liver metastasis
Authors
Yu Zhang
Qianshi Zhang
Mengyang Zhang
Menglang Yuan
Zhaohui Wang
Jingbo Zhang
Xu Zhou
Yinan Zhang
Fang Lin
Heya NA
Shuangyi Ren
Yunfei Zuo
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0639-2

Other articles of this Issue 1/2017

Molecular Cancer 1/2017 Go to the issue

Research

Overexpression of lncRNA IGFBP4–1 reprograms energy metabolism to promote lung cancer progression

Review

EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression

Letter to the Editor

Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors

Research

BMI1, a new target of CK2α

Research

IGF2BP3 functions as a potential oncogene and is a crucial target of miR-34a in gastric carcinogenesis

Review

Dysregulated expression of long noncoding RNAs in gynecologic cancers
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