구강편평상피세포암종에서 shikonin에 의한 상피간엽이행 억제
Shikonin inhibits the Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma
0
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
구강암은 주변 근육이나 골조직으로의 침습과 경부 림프절로 전이가 빈번히 일어나며, 전이가 일어난 환자의 5년 생존율은 약 40%로, 환자의 예후 개선을 위해 전이를 억제하는 항암제의 개발이 필요한 실정이다. 상피간엽이행 (EMT)이 일어난 세포에서는 이동성과 침습성이 증가하고, 암세포가 새로운 기관으로 전이가 일어나게 된다. 따라서, EMT를 억제하는 것은 암세포의 전이를 억제하는 치료 방법으로 고려 되고 있다. Shikonin은 지치에서 분리 정제된 물질로 항염증 효과가 널리 알려져 있다. 최근 shikonin은 다양한 암세포에서 세포자멸사 및 세포주기정지를 유도하고, 폐 및 위암세포의 전이성을 상실시키는 것이 밝혀졌다. 하지만 여전히 shikonin이 구강암에서 항전이 효과는 아직 불분명하다. 따라서 본 연구에서는 shikonin이 처리된 구강암 세포주에 대한 EMT 억제의 억제 효과를 확인 하였다. 본 연구에서 사용된 구강암 세포주 CAL-27로 세포생존율 및 세포증식율, 세포이동 및 침습, 단백질 및유전자의 발현을 확인하였다. CAL-27 세포는 shikonin 처리에 의해 생존율 및 증식율이 억제되었다. 또한, shikonin은 wound-healing 및 transwell invasion assay를 통해 CAL-27 세포의 이동 및 침습을 억제 하는것을 확인 하였다. Shikonin은 CAL-27 세포에서 epithelial marker 인 E-cadherin 의 protein 발현을 증가시켰으며, mesenchymal marker 인 N-cadherin, Snail 및 Slug 의 protein 및 RNA 발현을 감소 시켰다. 따라서, shikonin은 구강암세포주인 CAL-27의 상피간엽이행을 억제 함을 알 수 있었으며, 본 연구 결과는shikonin이 항전이성을 가지는 항암제로서의 가능성을 시사한다.
Abstract
Oral cancer invades the surrounding muscles and bone tissue and metastasizes to the cervical lymph nodes. The 5-year survival rate of patients with metastases is about 40%, and it is necessary to develop anticancer drugs that suppress metastasis to improve the prognosis of patients. In epithelial-mesenchymal transition (EMT), the squamous cancer cells have mobility, which increases the invasiveness and metastasis to new organs. Therefore, EMT inhibition is considered a therapeutic method for inhibiting the metastasis of cancer cells. Shikonin has been isolated and purified from Lithospermum erythrorhizon Sieb. et Zucc and is widely known for its anti-inflammatory effect. Recently, shikonin has been shown to induce apoptosis and cell cycle arrest in various cancer cells and to inhibit the metastatic properties of lung and gastric cancer cells. However, the effects of shikonin on oral cancer are still unclear. Therefore, we investigated the effect of EMT inhibition on shikonin-treated oral cancer cell line, CAL-27 cells. Shikonin treatment inhibited the viability and proliferation of CAL-27 cells. In addition, shikonin inhibited their migration and invasion in wound-healing and transwell invasion assays. Shikonin increased the protein expression of E-cadherin, an epithelial marker in CAL-27 cells, and decreased the protein and RNA expression of mesenchymal markers like N-cadherin, Snail, and Slug. Therefore, shikonin inhibited the epithelial-mesenchymal metastasis of oral cancer cell line CAL-27, suggesting that it may be an anticancer agent with an anti-metastatic effect.
참고문헌 (33)
- Rivera C, "Essentials of oral cancer", Int J Clin Exp Pathol, 8, pp.11884~11894 (2015)
- Waruna Lakmal Dissanayaka, "Clinical and histopathologic parameters in survival of oral squamous cell carcinoma", Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 113(4), pp.518~525 (2012), Elsevier BV[DOI]
- Fabio Ramoa Pires, "Oral squamous cell carcinoma: clinicopathological features from 346 cases from a single Oral Pathology service during an 8-year period", Journal of Applied Oral Science, 21(5), pp.460~467 (2013), FapUNIFESP (SciELO)[DOI]
- Bo Wang, "The recurrence and survival of oral squamous cell carcinoma: a report of 275 cases", Chinese Journal of Cancer, 32(11), pp.614~618 (2013), Editorial Office of Chinese Journal of Cancer[DOI]
- Ken Omura, "Current status of oral cancer treatment strategies: surgical treatments for oral squamous cell carcinoma", International Journal of Clinical Oncology, 19(3), pp.423~430 (2014), Springer Science and Business Media LLC[DOI]
- 류선열, "구강암 환자에 대한 후향적 연구", 대한구강악안면외과학회지, 22, pp.643~658 (1996)
- Savagner P, "The epithelial–mesenchymal transition (EMT) phenomenon", Annals of oncology, 21, pp.vii89~vii92 (2010)[DOI]
- Brabletz T, "EMT in cancer", Nature Reviews Cancer, 18, pp.128~ (2018)
- Xin Chen, "Cellular pharmacology studies of shikonin derivatives", Phytotherapy Research, 16(3), pp.199~209 (2002), Wiley[DOI]
- Fujita Y, "Production of shikonin derivatives by cell suspension cultures of Lithospermum erythrorhizon", Plant Cell Reports, 1, pp.61~63 (1981)
- A ASSIMOPOULOU, "Antioxidant activities of alkannin, shikonin and Alkanna tinctoria root extracts in oil substrates", Food Chemistry, 87(3), pp.433~438 (2004), Elsevier BV[DOI]
- Lee Y-S, "The mechanism underlying the antibacterial activity of Shikonin against methicillin-resistant Staphylococcus aureus", Evidence-Based Complementary and Alternative Medicine (2015)[DOI]
- V. Papageorgiou, "Alkannins and Shikonins: A New Class of Wound Healing Agents", Current Medicinal Chemistry, 15(30), pp.3248~3267 (2008), Bentham Science Publishers Ltd[DOI]
- Wan-Rong Huang, "Shikonin Inhibits the Proliferation of Human Lens Epithelial Cells by Inducing Apoptosis through ROS and Caspase-Dependent Pathway", Molecules, 19(6), pp.7785~7797 (2014), MDPI AG[DOI]
- HUILING JING, "Shikonin induces apoptosis of HaCaT cells via the mitochondrial, Erk and Akt pathways", Molecular Medicine Reports, 13(4), pp.3009~3016 (2016), Spandidos Publications[DOI]
- 고현석, "Shikonin Induces Apoptotic Cell Death via Regulation of p53 and Nrf2 in AGS Human Stomach Carcinoma Cells", Biomolecules & Therapeutics, 24(5), pp.501~509 (2016), 한국응용약물학회
- Min Ruan, "Growth inhibition and induction of apoptosis in human oral squamous cell carcinoma Tca-8113 cell lines by shikonin was partly through the inactivation of NF-κB pathway", Phytotherapy Research, 22(3), pp.407~415 (2008), Wiley[DOI]
- Rong Tian, "Shikonin causes cell-cycle arrest and induces apoptosis by regulating the EGFR–NF-κB signalling pathway in human epidermoid carcinoma A431 cells", Bioscience Reports, 35(2) (2015), Portland Press Ltd.[DOI]
- Yei-San Hsieh, "Shikonin Inhibited Migration and Invasion of Human Lung Cancer Cells via Suppression of c-Met-Mediated Epithelial-to-Mesenchymal Transition", Journal of Cellular Biochemistry, 118(12), pp.4639~4651 (2017), Wiley[DOI]
- Ji Ping Liu, "Shikonin inhibits the cell viability, adhesion, invasion and migration of the human gastric cancer cell line MGC-803 via the Toll-like receptor 2", nuclear factor-kappa B pathway, 2015, pp.67(8), 1143~1155[DOI]
- 오상헌, "Mechanism Underlying Shikonin-induced Apoptosis and Cell Cycle Arrest on SCC25 Human Tongue Squamous Cell Carcinoma Cell Line", International Journal of Oral Biology, 40(1), pp.51~61 (2015), 대한구강생물학회[DOI]
- Michael Zeisberg, "Biomarkers for epithelial-mesenchymal transitions", Journal of Clinical Investigation, 119(6), pp.1429~1437 (2009), American Society for Clinical Investigation[DOI]
- Sam M. Janes, "New roles for integrins in squamous-cell carcinoma", Nature Reviews Cancer, 6(3), pp.175~183 (2006), Springer Science and Business Media LLC[DOI]
- Lai W-W, "Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-κB and matrix metalloproteinase-2", -9 signaling pathways, 2013, pp.33, 1941~1950
- Ming-Hsien Chien, "Dioscorea nipponica Makino inhibits migration and invasion of human oral cancer HSC-3 cells by transcriptional inhibition of matrix metalloproteinase-2 through modulation of CREB and AP-1 activity", Food and Chemical Toxicology, 50(3-4), pp.558~566 (2012), Elsevier BV[DOI]
- Yongwei Wang, "Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: Involvement of NF-κB signaling pathway", Biochemical Pharmacology, 88(3), pp.322~333 (2014), Elsevier BV[DOI]
- Guo X, "Clinical trial on the effects of shikonin mixture on later stage lung cancer", Zhong xi yi jie he za zhi Chinese journal of modern developments in traditional medicine, 11, pp.598~599 (1991)
- Yue HOU, "Effect of Shikonin on Human Breast Cancer Cells Proliferation and Apoptosis In Vitro", YAKUGAKU ZASSHI, 126(12), pp.1383~1386 (2006), Pharmaceutical Society of Japan[DOI]
- S.M.K Rates, "Plants as source of drugs", Toxicon, 39(5), pp.603~613 (2001), Elsevier BV[DOI]
- J. L. Sebaugh, "Guidelines for accurate EC50", IC50 estimation, 2011, pp.10(2), 128~134[DOI]
- Raghu Kalluri, "EMT: When epithelial cells decide to become mesenchymal-like cells", Journal of Clinical Investigation, 119(6), pp.1417~1419 (2009), American Society for Clinical Investigation[DOI]
- Raghu Kalluri, "The basics of epithelial-mesenchymal transition", Journal of Clinical Investigation, 119(6), pp.1420~1428 (2009), American Society for Clinical Investigation[DOI]
- Ugo Cavallaro, "Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough", Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1552(1), pp.39~45 (2001), Elsevier BV[DOI]