Myeloid cell leukemia-1 promotes epithelial-mesenchymal transition of human gastric cancer cells

Lee,Wan-Sik; Kim,Nuri; Park,Young-Ran; Oh,Hyung-Hoon; Myung,Eun; Kim,Seung-Hun; Yu,Hyung-Min; Kim,Mi-Young; Oak,Chan-Young; Chung,Cho-Yun; Park,Hyung‑Chul; Myung,Dae-Seong; Cho,Sung-Bum; Joo,Young-Eun

doi:10.3892/or.2015.4040

August-2015 Volume 34 Issue 2

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

August-2015 Volume 34 Issue 2

Full Size Image

Article

Myeloid cell leukemia-1 promotes epithelial-mesenchymal transition of human gastric cancer cells

Authors:
- Wan-Sik Lee
- Nuri Kim
- Young-Ran Park
- Hyung-Hoon Oh
- Eun Myung
- Seung-Hun Kim
- Hyung-Min Yu
- Mi-Young Kim
- Chan-Young Oak
- Cho-Yun Chung
- Hyung‑Chul Park
- Dae-Seong Myung
- Sung-Bum Cho
- Young-Eun Joo
View Affiliations / Copyright

Affiliations: Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
Pages: 1011-1016
|
Published online on: June 8, 2015

https://doi.org/10.3892/or.2015.4040
Expand metrics +

Abstract

Epithelial-mesenchymal transition (EMT) is a critical process that occurs during cancer progression, and cancer stem cells have been shown to acquire the EMT phenotype. Myeloid cell leukemia-1 (Mcl-1) has been implicated in cancer progression and is overexpressed in a variety of human cancers. However, the interaction between Mcl-1 and EMT in human gastric cancer (GC) is unclear. We investigated the impact of Mcl-1 expression levels on EMT and the underlying signaling pathways in human GC cells. We used the human GC cell lines, AGS and SNU638, and small interfering RNAs (siRNAs) to evaluate the effects of Mcl-1 knockdown on cell adhesion, migration and invasion. Expression of Mcl-1 and other target genes was determined using reverse transcription‑polymerase chain reaction assays and western blotting. The results revealed that expression levels of Mcl-1 mRNA and protein in the AGS and SNU638 cells were reduced following transfection with Mcl-1 siRNAs. Knockdown of Mcl-1 led to increased cellular adhesion to fibronectin and collagen. Expression levels of vimentin, MMP-2, MMP-9 and Snail protein were decreased following knockdown of Mcl-1. However, expression of E-cadherin was increased in the AGS cells following knockdown of Mcl-1. The expression of cancer stemness markers, such as CD44 and CD133, was not altered by knockdown of Mcl-1. Knockdown of Mcl-1 suppressed tumor cell migration and invasion in both human GC cell lines. Signaling cascades, including the β-catenin, MEK1/2, ERK1/2 and p38 pathways, were significantly blocked by knockdown of Mcl-1. Our results indicate that Mcl-1 expression induces EMT via β-catenin, MEK1/2 and MAPK signaling pathways, which subsequently stimulates the invasive and migratory capacity of human GC cells.

View Figures

View References

1	Kuwahara A, Takachi R, Tsubono Y, Sasazuki S, Inoue M and Tsugane S; JPHC Study Group: Socioeconomic status and gastric cancer survival in Japan. Gastric Cancer. 13:222–230. 2010. View Article : Google Scholar : PubMed/NCBI
2	Krejs GJ: Gastric cancer: Epidemiology and risk factors. Dig Dis. 28:600–603. 2010. View Article : Google Scholar : PubMed/NCBI
3	Tan IB, Ng I, Tai WM and Tan P: Understanding the genetic basis of gastric cancer: recent advances. Expert Rev Gastroenterol Hepatol. 6:335–341. 2012. View Article : Google Scholar : PubMed/NCBI
4	Ola MS, Nawaz M and Ahsan H: Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 351:41–58. 2011. View Article : Google Scholar : PubMed/NCBI
5	Llambi F and Green DR: Apoptosis and oncogenesis: Give and take in the BCL-2 family. Curr Opin Genet Dev. 21:12–20. 2011. View Article : Google Scholar : PubMed/NCBI
6	Weyhenmeyer B, Murphy AC, Prehn JH and Murphy BM: Targeting the anti-apoptotic Bcl-2 family members for the treatment of cancer. Exp Oncol. 34:192–199. 2012.PubMed/NCBI
7	Davids MS and Letai A: Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 30:3127–3135. 2012. View Article : Google Scholar : PubMed/NCBI
8	Thomas LW, Lam C and Edwards SW: Mcl-1; the molecular regulation of protein function. FEBS Lett. 584:2981–2989. 2010. View Article : Google Scholar : PubMed/NCBI
9	Akgul C: Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci. 66:1326–1336. 2009. View Article : Google Scholar
10	Mandelin AM II and Pope RM: Myeloid cell leukemia-1 as a therapeutic target. Expert Opin Ther Targets. 11:363–373. 2007. View Article : Google Scholar : PubMed/NCBI
11	Perciavalle RM and Opferman JT: Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol. 23:22–29. 2013. View Article : Google Scholar
12	Zhang T, Zhao C, Luo L, Zhao H, Cheng J and Xu F: The expression of Mcl-1 in human cervical cancer and its clinical significance. Med Oncol. 29:1985–1991. 2012. View Article : Google Scholar
13	Luo L, Zhang T, Liu H, Lv T, Yuan D, Yao Y, Lv Y and Song Y: miR-101 and Mcl-1 in non-small-cell lung cancer: Expression profile and clinical significance. Med Oncol. 29:1681–1686. 2012. View Article : Google Scholar
14	Henderson-Jackson EB, Helm J, Ghayouri M, Hakam A, Nasir A, Leon M, Bui M, Yeatman T and Coppola D: Correlation between Mcl-1 and pAKT protein expression in colorectal cancer. Int J Clin Exp Pathol. 3:768–774. 2010.PubMed/NCBI
15	Likui W, Qun L, Wanqing Z, Haifeng S, Fangqiu L and Xiaojun L: Prognostic role of myeloid cell leukemia-1 protein (Mcl-1) expression in human gastric cancer. J Surg Oncol. 100:396–400. 2009. View Article : Google Scholar : PubMed/NCBI
16	Maeta Y, Tsujitani S, Matsumoto S, Yamaguchi K, Tatebe S, Kondo A, Ikeguchi M and Kaibara N: Expression of Mcl-1 and p53 proteins predicts the survival of patients with T3 gastric carcinoma. Gastric Cancer. 7:78–84. 2004. View Article : Google Scholar : PubMed/NCBI
17	Tsujitani S, Saito H, Wakatsuki T, Ikeguchi M, Shirabe K, Morita M, Kakeji Y, Yano T and Maehara Y: Relationship between expression of apoptosis-related proteins and the efficacy of postoperative chemotherapy in patients with T3 gastric cancer. Surg Today. 42:225–232. 2012. View Article : Google Scholar
18	Steinestel K, Eder S, Schrader AJ and Steinestel J: Clinical significance of epithelial-mesenchymal transition. Clin Transl Med. 3:172014. View Article : Google Scholar : PubMed/NCBI
19	Davis FM, Stewart TA, Thompson EW and Monteith GR: Targeting EMT in cancer: Opportunities for pharmacological intervention. Trends Pharmacol Sci. 35:479–488. 2014. View Article : Google Scholar : PubMed/NCBI
20	Peng Z, Wang CX, Fang EH, Wang GB and Tong Q: Role of epithelial-mesenchymal transition in gastric cancer initiation and progression. World J Gastroenterol. 20:5403–5410. 2014. View Article : Google Scholar : PubMed/NCBI
21	Guarino M, Rubino B and Ballabio G: The role of epithelial-mesenchymal transition in cancer pathology. Pathology. 39:305–318. 2007. View Article : Google Scholar : PubMed/NCBI
22	Natalwala A, Spychal R and Tselepis C: Epithelial-mesenchymal transition mediated tumourigenesis in the gastrointestinal tract. World J Gastroenterol. 14:3792–3797. 2008. View Article : Google Scholar : PubMed/NCBI
23	Townson JL and Chambers AF: Dormancy of solitary metastatic cells. Cell Cycle. 5:1744–1750. 2006. View Article : Google Scholar : PubMed/NCBI
24	Chambers AF, Groom AC and MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2:563–572. 2002. View Article : Google Scholar : PubMed/NCBI
25	Ombrato L and Malanchi I: The EMT universe: space between cancer cell dissemination and metastasis initiation. Crit Rev Oncog. 19:349–361. 2014. View Article : Google Scholar : PubMed/NCBI
26	Findlay VJ, Wang C, Watson DK and Camp ER: Epithelial-to-mesenchymal transition and the cancer stem cell phenotype: Insights from cancer biology with therapeutic implications for colorectal cancer. Cancer Gene Ther. 21:181–187. 2014. View Article : Google Scholar : PubMed/NCBI
27	Liu X and Fan D: The epithelial-mesenchymal transition and cancer stem cells: functional and mechanistic links. Curr Pharm Des. 21:1279–1291. 2015. View Article : Google Scholar
28	Lindsey S and Langhans SA: Crosstalk of oncogenic signaling pathways during epithelial-mesenchymal transition. Front Oncol. 4:3582014. View Article : Google Scholar
29	Lee JM, Dedhar S, Kalluri R and Thompson EW: The epithelial-mesenchymal transition: New insights in signaling, development, and disease. J Cell Biol. 172:973–981. 2006. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Myeloid cell leukemia-1 promotes epithelial-mesenchymal transition of human gastric cancer cells

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Related Articles