Suppression of Migration and Invasion by Alnus hirsuta in Human Hepatocellular Carcinoma Cells
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Hepatocellular carcinoma (HCC) has a poor prognosis and high metastasis and recurrence rates. Although extracts of Alnus hirsuta (Turcz. ex Spach) Rupr. (AH) have been demonstrated to possess potential anti-inflammatory and anti-cancer activities, the underlying mechanism of AH in HCC treatment remains to be elucidated. We investigated the effects and potential mechanisms of AH on migration and invasion of Hep3B cells. Within the non-cytotoxic concentration range, AH significantly inhibited motility and invasiveness of Hep3B cells in a concentration-dependent manner. Inhibitory effects of AH on cell invasiveness are associated with tightening of tight junctions (TJs), as demonstrated by an increase in transepithelial electrical resistance. Immunoblotting indicated that AH decreased levels of claudins, which form major components of TJs and play key roles in the control and selectivity of paracellular transport. Furthermore, AH inhibited the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and simultaneously increased the levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These effects were related to inactivation of the phosphoinositide 3-kinase (PI3K)/AKT pathway in Hep3B cells. Therefore, AH inhibits migration and invasion of Hep3B cells by inhibiting the activity of MMPs and tightening TJs through suppression of claudin expression, possibly by suppressing the PI3K/AKT signaling pathway.
Abstract
Hepatocellular carcinoma (HCC) has a poor prognosis and high metastasis and recurrence rates. Although extracts of Alnus hirsuta (Turcz. ex Spach) Rupr. (AH) have been demonstrated to possess potential anti-inflammatory and anti-cancer activities, the underlying mechanism of AH in HCC treatment remains to be elucidated. We investigated the effects and potential mechanisms of AH on migration and invasion of Hep3B cells. Within the non-cytotoxic concentration range, AH significantly inhibited motility and invasiveness of Hep3B cells in a concentration-dependent manner. Inhibitory effects of AH on cell invasiveness are associated with tightening of tight junctions (TJs), as demonstrated by an increase in transepithelial electrical resistance. Immunoblotting indicated that AH decreased levels of claudins, which form major components of TJs and play key roles in the control and selectivity of paracellular transport. Furthermore, AH inhibited the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and simultaneously increased the levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These effects were related to inactivation of the phosphoinositide 3-kinase (PI3K)/AKT pathway in Hep3B cells. Therefore, AH inhibits migration and invasion of Hep3B cells by inhibiting the activity of MMPs and tightening TJs through suppression of claudin expression, possibly by suppressing the PI3K/AKT signaling pathway.
참고문헌 (49)
- 안미연, "댕댕이나무(Lonicera caerulea)의 대장암세포 생육억제 활성", 한국자원식물학회지, 33(4), pp.263~270 (2020), 한국자원식물학회
- Angelow, S., "Claudins and paracellular transport: an update", Curr. Opin. Nephrol. Hypertens, 16, pp.459~464 (2007)
- Aoki, T., "Triterpenoids, diarylheptanoids and their glycosides in the flowers of Alnus speies", Phytochemistry, 29, pp.3611~3614 (1990)
- 최선은, "Diarylheptanoids from the Bark of Alnus pendula Matsumura", Natural Product Sciences, 18(2), pp.106~110 (2012), 한국생약학회[DOI]
- Dilly, A. K., "Platelet-type 12-lipoxygenase induces MMP9 expression and cellular invasion via activation of PI3K", Akt, Int. J. Cancer, pp.2013, 133[DOI]
- Du, H., "Berberine suppresses EMT in liver and gastric carcinoma cells through combination with TGF-β regulating TGF-β", smad Pathway, 2021, pp.2021, 2337818~
- Egeblad, M., "New functions for the matrix metalloproteinases in cancer progression", Nat. Rev. Cancer, 2, pp.161~174 (2002)
- Furuse, M., "Convertsion of Zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells", J. Cell Biol, 153, pp.263~272 (2001)
- Gibbs, D. F., "Characterization of matrix metalloproteinases produced by rat alveolar macrophages", Am J. Respir. Cell Mol. Biol, 20, pp.1136~1144 (1999)
- Grant-Tschudy, K. S., "Effect of oestradiol on mouse uterine epithelial cell tumour necrosis factor-alpha release is mediated through uterine stromal cells", Immunology, 115, pp.99~107 (2005)
- Guo, J. X., "International Collation of Traditional and Folk Medicine. Vol. 4" (2001), World Scientific Publishing
- Guo, J. X., "International Collation of Traditional and Folk Medicine: Northeast Asia. Vol.4" (2001), World Scientific Publishing
- Hanahan, D., "Hallmarks of cancer: the next generation", Cell, 144, pp.646~674 (2011)
- Hsu, R. Y., "LPS-induced TLR4 signaling in human colorectal cancer cells increases β1 integrinmediated cell adhesion and liver metastasis", Cancer Res, 71, pp.1989~1998 (2011)
- Jeong, D. W., "Diarylheptanoids from the stem barks of Alnus hirsuta var sibirica", Korean J. Pharmacogn, 31, pp.28~33 (2000)
- John, A., "The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis", Pathol. Oncol. Res, 7, pp.14~23 (2001)
- Joo, S. S., "Suppression of T cell activation by hirsutenone, isolated from the bark of Alnus japonica, and its therapeutic advantages for atopic dermatitis", Eur. J. Pharmacol, 614, pp.98~105 (2009)
- Kessenbrock, K., "Matrix metalloproteinases : regulators of the tumor microenvironment", Cell, 141, pp.52~67 (2010)
- Khasigov, P. Z., "Role of matrix metalloproteinases and their inhibitors in tumor invasion and metastasis", Biochemistry Mosc, 68, pp.711~717 (2003)
- Krause, G., "Structure and function of claudins", Biochim. Biophys. Acta, 1778, pp.631~645 (2008)
- Lambert, E., "TIMPs as multifacial proteins", Crit. Rev. Oncol. Hematol, 49, pp.187~198 (2004)
- Lee, M. N., "Antiadipogenic diarylheptanoids from Alnus hirsuta var sibirica on 3T3-L1 cells", Bioorg. Med. Chem. Lett, 23, pp.2069~2073 (2013)
- Lee, M. W., "Flavonoids from the leaves of Alnus hirsuta", Yakhak-Hoegi, 43, pp.547~552 (1999)
- Lee, M. W., "Hirsunin, an ellagitannin with a diarylheptanoid moiety, from Alnus hirsuta var microphylla", Phytochemistry, 31, pp.967~970 (1992)
- Lee, O., "Effect of pedunculagin investigated by non-invasive evaluation on atopic-like dermatitis in NC", Nga mice, 2010, pp.16, 371~377
- Lee, S. J., "Korea Folk Medicine", pp.40~ (1996), Seoul National University Publishing Center
- Li, C., "LFG-500 inhibits the invasion of cancer cells via down-regulation of PI3K", AKT, PLoS ONE, pp.2014, 9[DOI]
- Liu, G., "Vascular endothelial growth factor B coordinates metastasis of non-small cell lung cancer", Tumour Biol, 36, pp.2185~2191 (2015)
- Mattiolo, P., "Hepatoid tumors of the gastrointestinal", pancreatobiliary district: morphology, immunohistochemistry, and molecular profiles, 2023, pp.132, 169~175
- Mook, O. R., "The role of gelatinases in colorectal cancer progression and metastasis", Biochim. Biophys. Acta, 1705, pp.69~89 (2004)
- Morin, P. J, "Claudin proteins in human cancer: Promising new targets for diagnosis and therapy", Cancer Res, 65, pp.9603~9606 (2005)
- O’Leary, D. P., "TLR-4 signaling accelerates colon cancer cell adhesion via NF-κB mediated transcriptional up-regulation of Nox-1", PLoS ONE, 7, pp.e44176~ (2012)
- 오현경, "전북 고산자연휴양림 일대의 관속식물상 연구 -식재종을 제외한 야생식물을 중심으로-", 한국자원식물학회지, 19(5), pp.617~10 (2006), 한국자원식물학회
- 오현경, "금원산 생태수목원 조성 부지의 관속식물상 연구", 한국자원식물학회지, 21(2), pp.117~127 (2008), 한국자원식물학회
- Park, S. Y., "Aromaticturmerone attenuates invasion and expression of MMP-9 and COX-2 through inhibition of NF-κB activation in TPA-induced breast cancer cells", J. Cell. Biochem, 113, pp.3653~3662 (2012)
- Rubenwolf, P., "Permeability of differentiated human urothelium in vitro", Methods Mol. Biol, 763, pp.207~222 (2011)
- Schneeberger, E. E., "The tight junction: a multifunctional complex", Am. J. Physiol. Cell Physiol, 286, pp.C1213~C1228 (2004)
- Singh, A. B., "Claudin family of proteins and cancer an overview", J. Oncol, 2010, pp.541957~ (2010)
- Soler, A. P., "Increased tight junctional permeability is associated with the development of colon cancer", Carcinogenesis, 20, pp.1425~1431 (1999)
- 송하용, "Suppression of TNF-alpha-induced MMP-9 expression by a cell-permeable superoxide dismutase in keratinocytes", BMB Reports, 44(7), pp.462~467 (2011), 생화학분자생물학회
- Suga, T., "Chemical constituents of the male flower of Alnus pendula (Betulaceae)", Bull. Chem. Soc. Jpn, 45, pp.2058~2060 (1972)
- caused by the interaction of hirsutoside and catechol oxidase after cutting the woods, "Mokuzai Gakkaishi", 1984, 601~607
- Tsukita, S., "Pores in the wall: claudins constitute tight junction strands containing aqueous pores", J. Cell Biol, 149, pp.13~16 (2000)
- Turksen, K., "Junctions gone bad: claudins and loss of the barrier in cancer", Biochim. Biophys. Acta, 1816, pp.73~79 (2011)
- Utech, M., "Tight junctions and cell-cell interactions", Methods Mol. Biol, 341, pp.185~195 (2006)
- Uzui, H., "Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque: role of activated macrophages and inflammatory cytokines", Circulation, 106, pp.3024~3030 (2002)
- Vihinen, P., "Matrix metalloproteinases as therapeutic targets in cancer", Curr. Cancer Drug Targets, 5, pp.203~220 (2005)
- Vu, T. H., "Matrix metalloproteinases : effectors of development and normal physiology", Genes Dev, 14, pp.2123~2133 (2000)
- Wei Zhu, "5-Formylhonokiol exerts anti-angiogenesis activity via inactivating the ERK signaling pathway", Experimental and Molecular Medicine, 43(3), pp.146~152 (2011), 생화학분자생물학회