Association between hyperpolarization-activated channel in interstitial cells of Cajal and gastrointestinal dysmotility induced by malignant ascites

Guo,Tieyun; Li,Jiade; Li,Jing; Kong,Dan; Bi,Chunli; He,Zheng; Tang,Dai; Jin,Xiaoming; Jin,Lianhong

doi:10.3892/ol.2017.5652

Association between hyperpolarization-activated channel in interstitial cells of Cajal and gastrointestinal dysmotility induced by malignant ascites

Authors:
- Tieyun Guo
- Jiade Li
- Jing Li
- Dan Kong
- Chunli Bi
- Zheng He
- Dai Tang
- Xiaoming Jin
- Lianhong Jin
View Affiliations

Affiliations: Department of Histology and Embryology, Basic Medical Science College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Department of Gynecology, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
Published online on: January 25, 2017 https://doi.org/10.3892/ol.2017.5652
Pages: 1601-1608
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Advanced malignant ascites is accompanied by gastrointestinal dysmotility, and patients often feel abdominal pain, abdominal distention, nausea and constipation. Gastrointestinal dysmotility is not only painful for the patients, but it reduces the absorption of nutrients and affects the physical recovery of patients with malignant ascites. It is reported that changes in interstitial cells of Cajal (ICCs) are responsible for the gastrointestinal dysmotility induced by malignant ascites, but the mechanism is not completely understood. The present study observed a significantly decreased expression of ion channels, including hyperpolarization‑activated cyclic nucleotide‑gated potassium channel 2 (HCN2) and cyclic adenosine monophosphate, in the condition of malignant ascites. Using electrophysiology, it was identified that malignant ascites led to lower amplitude and slower frequency signals in cells of the small intestine. In addition, when ICCs were cultured with malignant ascites in vitro, the expression of HCN2 of ICCs was significantly reduced, and the data of flow cytometry revealed that the Ca2+ concentration of ICCs was also decreased. The results of electron microscopy analysis demonstrated the nuclei of ICCs were pyknotic, and the processes of ICCs were reduced in malignant ascites. The present study suggests the small intestinal dysmotility caused by malignant ascites may be associated with changes in HCN2 of ICCs, which offers a potential therapeutic target for gastrointestinal dysmotility in advanced malignant ascites.

View Figures

View References

1	Becker G, Galandi D and Blum HE: Malignant ascites: Systematic review and guideline for treatment. Eur J Cancer. 42:589–597. 2006. View Article : Google Scholar : PubMed/NCBI
2	Sangisetty SL and Miner TJ: Malignant ascites: A review of prognostic factors, pathophysiology and therapeutic measures. World J Gastrointest Surg. 4:87–95. 2012. View Article : Google Scholar : PubMed/NCBI
3	Zheng H, He Y, Tong J, Sun L, Yang D, Li H, Ao N, Jin X and Zhang Q: Is gastrointestinal dysfunction induced by gastric cancer peritoneal metastasis relevant to impairment of interstitial cells of Cajal? Clin Exp Metastasis. 28:291–299. 2011. View Article : Google Scholar : PubMed/NCBI
4	Li J, Kong D, He Y, Wang X, Gao L, Li J, Yan M, Liu D, Wang Y, Zhang L and Jin X: The impact of inflammatory cells in malignant ascites on small intestinal ICCs' morphology and function. J Cell Mol Med. 19:2118–2127. 2015.PubMed/NCBI
5	Sanders KM, Ward SM and Koh SD: Interstitial cells: Regulators of smooth muscle function. Physiol Rev. 94:859–907. 2014. View Article : Google Scholar : PubMed/NCBI
6	Gomez-Pinilla PJ, Gibbons SJ, Bardsley MR, Lorincz A, Pozo MJ, Pasricha PJ, Van de Rijn M, West RB, Sarr MG, Kendrick ML, et al: Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol. 296:G1370–G1381. 2009. View Article : Google Scholar : PubMed/NCBI
7	Koh SD, Sanders KM and Ward SM: Spontaneous electrical rhythmicity in cultured interstitial cells of cajal from the murine small intestine. J Physiol. 513:203–213. 1998. View Article : Google Scholar : PubMed/NCBI
8	d'antonio C, Wang B, McKay C and Huizinga JD: Substance P activates a non-selective cation channel in murine pacemaker ICC. Neurogastroenterol Motil. 21:985-e79. 2009.
9	Huizinga JD, Zarate N and Farrugia G: Physiology, injury, and recovery of interstitial cells of Cajal: Basic and clinical science. Gastroenterology. 137:1548–1556. 2009. View Article : Google Scholar : PubMed/NCBI
10	Strege PR, Ou Y, Sha L, Rich A, Gibbons SJ, Szurszewski JH, Sarr MG and Farrugia G: Sodium current in human intestinal interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol. 285:G1111–G1121. 2003. View Article : Google Scholar : PubMed/NCBI
11	Ward SM and Sanders KM: Involvement of intramuscular interstitial cells of Cajal in neuroeffector transmission in the gastrointestinal tract. J Physiol. 576:675–682. 2006. View Article : Google Scholar : PubMed/NCBI
12	Sanders KM and Ward SM: Interstitial cells of Cajal: A new perspective on smooth muscle function. J Physiol. 576:721–726. 2006. View Article : Google Scholar : PubMed/NCBI
13	O'Donnell AM, Coyle D and Puri P: Decreased expression of hyperpolarisation-activated cyclic nucletide-gated channel 3 in Hirschsprung's disease. World J Gastroenterol. 21:5635–5640. 2015. View Article : Google Scholar : PubMed/NCBI
14	Shahi PK, Choi S, Zuo DC, Kim MY, Park CG, Kim YD, Lee J, Park KJ, So I and Jun JY: The possible roles of hyperpolatization-activated cyclic nucleotide channels in regulating pacemaker activity in colonic interstitial cells of Cajal. J Gastroenterol. 49:1001–1010. 2014. View Article : Google Scholar : PubMed/NCBI
15	Harzheim D, Pfeiffer KH, Fabritz L, Kremmer E, Buch T, Waisman A, Kirchhof P, Kaupp UB and Seifert R: Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP. EMBO J. 27:692–703. 2008. View Article : Google Scholar : PubMed/NCBI
16	Zong X, Krause S, Chen CC, Krüger J, Gruner C, Cao-Ehlker X, Fenske S, Wahl-Schott C and Biel M: Regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by cCMP. J Biol Chem. 287:26506–26512. 2012. View Article : Google Scholar : PubMed/NCBI
17	DiFrancesco JC and DiFrancesco D: Dysfunctional HCN ion channels in neurological diseases. Front Cell Neurosci. 6:1742015. View Article : Google Scholar : PubMed/NCBI
18	Bernard M, Dejos C, Berges T, Regnacq M and Voisin P: Activation of rhodopsin gene transcription in cultured retinal precursors of chicken embryo: Role of Ca(2+) signaling and hyperpolarization-activated cation channels. J Neurochem. 129:85–98. 2014. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C (T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Pape HC: Queer current and pacemaker: The hyperpolarization-actived cation current in neurons. Annu Rev Physiol. 58:299–327. 1996. View Article : Google Scholar : PubMed/NCBI
21	DiFrancesco D and Tortora P: Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature. 351:145–147. 1991. View Article : Google Scholar : PubMed/NCBI
22	Chasen M and Bhargava R: Gastrointestinal symptoms, electrogastrography, inflammatory makers, and PG-SGA in patients with advanced cancer. Support Care Cancer. 20:1283–1290. 2012. View Article : Google Scholar : PubMed/NCBI
23	Lee JC, Thuneberg L, Berezin I and Huizinga JD: Generation of slow waves in membrane potential is an intrinsic property of interstitial cells of Cajal. Am J Physiol. 277:G409–G423. 1999.PubMed/NCBI
24	Tan YY, Ji ZL, Zhao G, Jiang JR, Wang D and Wang JM: Decreased SCF/c-kit signaling pathway contributes to loss of interstitial cells of Cajal in gallstone disease. Int J Clin Exp Med. 7:4099–4106. 2014.PubMed/NCBI
25	Kong D, Li J, Zhao B, Xia B, Zhang L, He Y, Wang X, Gao L, Wang Y, Jin X and Lou G: The effect of SCF and ouabain on small intestinal motility dysfunction induced by gastric cancer peritoneal metastasis. Clin Exp Metastasis. 32:267–277. 2015. View Article : Google Scholar : PubMed/NCBI
26	Singh RD, Gibbons SJ, Saravanaperumal SA, Du P, Hennig GW, Eisenman ST, Mazzone A, Hayashi Y, Cao C, Stoltz GJ, et al: Ano1, a Ca²⁺-activated Cl- channel, coordinates contractility in mouse intestine by Ca²⁺ transient coordination between interstitial cells of Cajal. J Physiol. 592:4051–4068. 2014. View Article : Google Scholar : PubMed/NCBI
27	Ward SM, Ordog T, Koh SD, Baker SA, Jun JY, Amberg G, Monaghan K and Sanders KM: Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. J Physiol. 525:355–361. 2000. View Article : Google Scholar : PubMed/NCBI
28	Drumm BT, Sergeant GP, Hollywood MA, Thornbury KT, Matsuda TT, Baba A, Harvey BJ and McHale NG: The effect of high [K(+)]o on spontaneous Ca(2+) waves in freshly isolated interstitial cells of Cajal from the rabbit urethra. Physiol Rep. 2:e002032014. View Article : Google Scholar : PubMed/NCBI
29	Zhu MH, Sung TS, O'Driscoll K, Koh SD and Sanders KM: Intracellular Ca(2+) release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal. Am J Physiol Cell Physiol. 308:C608–C620. 2015. View Article : Google Scholar : PubMed/NCBI
30	Zheng H, Park KS, Koh SD and Sanders KM: Expression and function of a T-type Ca²⁺ conductance in interstitial cells of Cajal of the murine small intestine. Am J Physiol Cell Physiol. 306:C705–C713. 2014. View Article : Google Scholar : PubMed/NCBI
31	Biel M, Schneider A and Wahl C: Cardiac HCN channels: Structure, function, and modulation. Trends Cardiovasc Med. 12:206–212. 2002. View Article : Google Scholar : PubMed/NCBI
32	Notomi T and Shigemoto R: Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J Comp Neurol. 471:241–276. 2004. View Article : Google Scholar : PubMed/NCBI
33	Wang YP, Sun BY, Li Q, Dong L, Zhang GH, Grundy D and Rong WF: Hperpolarization-activated cyclic nucleotide-gated cation channel subtypes differentially modulate the excitability of murine small intestinal afferents. World J Gastroenterol. 18:522–531. 2012. View Article : Google Scholar : PubMed/NCBI
34	Yang S, Xiong CJ, Sun HM, Li XS, Zhang GQ, Wu B and Zhou DS: The distribution of HCN2-positive cells in the gastrointestinal tract of mice. J Anat. 221:303–310. 2012. View Article : Google Scholar : PubMed/NCBI
35	Biel M, Wahl-Schott C, Michalakis S and Zong X: Hyperpolarization-activated cation channels: From genes to function. Physiol Rev. 89:847–885. 2009. View Article : Google Scholar : PubMed/NCBI
36	He P, Deng J, Zhong X, Zhou Z, Song B and Li L: Identification of a hyperpolarization-activated cyclic nucleotide-gated channel and its subtypes in the urinary bladder of the rat. Urology. 79:1411.e7-e13. 2012. View Article : Google Scholar
37	Herrmann S, Schnorr S and Ludwig A: HCN channels-modulators of cardiac and neuronal excitability. Int J Mol Sci. 16:1429–1447. 2015. View Article : Google Scholar : PubMed/NCBI
38	Wainger BJ, DeGennaro M, Santoro B, Siegelbaum SA and Tibbs GR: Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature. 411:805–810. 2001. View Article : Google Scholar : PubMed/NCBI