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
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Metastasis | Research

A novel miR-365-3p/EHF/keratin 16 axis promotes oral squamous cell carcinoma metastasis, cancer stemness and drug resistance via enhancing β5-integrin/c-met signaling pathway

Authors: Wei-Chieh Huang, Te-Hsuan Jang, Shiao-Lin Tung, Tzu-Chen Yen, Shih-Hsuan Chan, Lu-Hai Wang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

Login to get access

Abstract

Background

Targeting the c-Met signaling pathway has become a therapeutic strategy in multiple types of cancer. We unveiled a novel c-Met regulating mechanism that could be applied as a modality for oral squamous cell carcinoma (OSCC) therapy.

Methods

Upregulation of keratin 16 (KRT16) was found by comparing isogenic pairs of low and high invasive human OSCC lines via microarray analysis. OSCC cells with ectopic expression or silencing of KRT16 were used to scrutinize functional roles and associated molecular mechanisms.

Results

We observed that high KRT16 expression significantly correlated with poorer pathological differentiation, advanced stages, increased lymph nodes metastasis, and decreased survival rate from several Taiwanese OSCC patient cohorts. We further revealed that miR-365-3p could target ETS homologous factor (EHF), a KRT16 transcription factor, to decrease migration, invasion, metastasis and chemoresistance in OSCC cells via inhibition of KRT16. Under confocal microscopic examination, c-Met was found possibly partially associates with KRT16 through β5-integrin. Colocalization of these three proteins may facilitate c-Met and β5-integrin–mediated signaling in OSCC cells. Depletion of KRT16 led to increased protein degradation of β5-integrin and c-Met through a lysosomal pathway leading to inhibition of their downstream Src/STAT3/FAK/ERK signaling in OSCC cells. Knockdown of KRT16 enhanced chemosensitivity of OSCC towards 5-fluorouracil (5-FU). Various combination of c-Met inhibitor (foretinib), protein tyrosine kinase inhibitor (genistein), β5-integrin antibody, and 5-FU markedly augmented cytotoxic effects in OSCC cells as well as tumor killing effects in vitro and in vivo.

Conclusions

Our data indicate that targeting a novel miR-365-3p/EHF/KRT16/β5-integrin/c-Met signaling pathway could improve treatment efficacy in OSCC.
Appendix
Available only for authorised users
Literature
1.
Ho P-S, Ko Y-C, Yang Y-HC, Shieh T-Y, Tsai C-C. The incidence of oropharyngeal cancer in Taiwan: an endemic betel quid chewing area. J Oral Pathol Med. 2002;31(4):213–9.PubMedCrossRef
2.
Chen Y-J, Chang JT-C, Liao C-T, Wang H-M, Yen T-C, Chiu C-C, Lu Y-C, Li H-F, Cheng A-J. Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci. 2008;99(8):1507–14.PubMedCrossRef
3.
Fan S, Tang Q-l, Lin Y-j, Chen W-l, Li J-s, Huang Z-q, Yang Z-h, Wang Y-y, Zhang D-m, Wang H-j, et al. A review of clinical and histological parameters associated with contralateral neck metastases in oral squamous cell carcinoma. Int J Oral Sci. 2011;3(4):180–91.PubMedPubMedCentralCrossRef
4.
Wang C, Liu XQ, Hou JS, Wang JN, Huang HZ. Molecular mechanisms of Chemoresistance in Oral Cancer. Chin J Dent Res. 2016;19(1):25–33.PubMed
5.
Karantza V. Keratins in health and cancer: more than mere epithelial cell markers. Oncogene. 2011;30(2):127–38.PubMedCrossRef
6.
Joosse SA, Hannemann J, Spötter J, Bauche A, Andreas A, Müller V, Pantel K. Changes in keratin expression during metastatic progression of breast Cancer: impact on the detection of circulating tumor cells. Clin Cancer Res. 2012;18(4):993–1003.PubMedCrossRef
7.
Fillies T, Werkmeister R, Packeisen J, Brandt B, Morin P, Weingart D, Joos U, Buerger H: Cytokeratin 8/18 expression indicates a poor prognosis in squamous cell carcinomas of the oral cavity. BMC Cancer 2006, 6:10–10.
8.
Hamakawa H, Bao Y, Takarada M, Fukuzumi M, Tanioka H. Cytokeratin expression in squamous cell carcinoma of the lung and oral cavity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;85(4):438–43.PubMedCrossRef
9.
Nievers MG, Schaapveld RQ, Oomen LC, Fontao L, Geerts D, Sonnenberg A. Ligand-independent role of the beta 4 integrin subunit in the formation of hemidesmosomes. J Cell Sci. 1998;111(12):1659–72.PubMed
10.
de Pereda JM, Lillo MP, Sonnenberg A. Structural basis of the interaction between integrin α6β4 and plectin at the hemidesmosomes. EMBO J. 2009;28(8):1180–90.PubMedPubMedCentralCrossRef
11.
Wilhelmsen K, Litjens SHM, Sonnenberg A. Multiple functions of the integrin α6β4 in epidermal homeostasis and tumorigenesis. Mol Cell Biol. 2006;26(8):2877–86.PubMedPubMedCentralCrossRef
12.
Seltmann K, Roth W, Loschke F, Lederer M, Hüttelmaier S, Magin TM. Keratins mediate localization of hemidesmosomes and repress cell motility. J Invest Dermatol. 2013;133(1):181–90.PubMedCrossRef
13.
Puri N, Khramtsov A, Ahmed S, Nallasura V, Hetzel JT, Jagadeeswaran R, Karczmar G, Salgia R. A selective small molecule inhibitor of c-met, PHA665752, inhibits Tumorigenicity and angiogenesis in mouse lung Cancer xenografts. Cancer Res. 2007;67(8):3529–34.PubMedCrossRef
14.
Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015;25(4):234–40.PubMedPubMedCentralCrossRef
15.
16.
Seltmann K, Cheng F, Wiche G, Eriksson JE, Magin TM. Keratins stabilize Hemidesmosomes through regulation of β4-integrin turnover. J Investig Dermatol. 2015;135(6):1609–20.PubMedCrossRef
17.
Huang W-C, Chan S-H, Jang T-H, Chang J-W, Ko Y-C, Yen T-C, Chiang S-L, Chiang W-F, Shieh T-Y, Liao C-T, et al. miRNA-491-5p and GIT1 serve as modulators and biomarkers for Oral squamous cell carcinoma invasion and metastasis. Cancer Res. 2014;74(3):751–64.PubMedCrossRef
18.
Tung SL, Huang WC, Hsu FC, Yang ZP, Jang TH, Chang JW, Chuang CM, Lai CR, Wang LH. miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERK pathway. Oncogenesis. 2017;6:e326.PubMedPubMedCentralCrossRef
19.
Booth BW, Boulanger CA, Anderson LH, Jimenez-Rojo L, Brisken C, Smith GH. Amphiregulin mediates self-renewal in an immortal mammary epithelial cell line with stem cell characteristics. Exp Cell Res. 2010;316(3):422–32.PubMedCrossRef
20.
21.
22.
Yoshioka T, Otero J, Chen Y, Kim Y-M, Koutcher JA, Satagopan J, Reuter V, Carver B, de Stanchina E, Enomoto K, et al. β4 Integrin signaling induces expansion of prostate tumor progenitors. J Clin Invest. 2013;123(2):682–99.PubMedPubMedCentral
23.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale C-M, Zhao X, Christensen J, et al. MET amplification leads to Gefitinib resistance in lung Cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43.PubMedCrossRef
24.
Barrow-McGee R, Kishi N, Joffre C, Ménard L, Hervieu A, Bakhouche BA, Noval AJ, Mai A, Guzmán C, Robbez-Masson L, et al. Beta 1-integrin–c-met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes. Nat Commun. 2016;7:11942.PubMedPubMedCentralCrossRef
25.
Tanida I, Minematsu-Ikeguchi N, Ueno T, Kominami E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy. 2005;1(2):84–91.PubMedCrossRef
26.
Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010;11(12):834–48.PubMedCrossRef
27.
Colomiere M, Ward AC, Riley C, Trenerry MK, Cameron-Smith D, Findlay J, Ackland L, Ahmed N. Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas. Br J Cancer. 2008;100:134.PubMedPubMedCentralCrossRef
28.
Bollrath J, Greten FR. IKK/NF-κB and STAT3 pathways: central signalling hubs in inflammation-mediated tumour promotion and metastasis. EMBO Rep. 2009;10(12):1314–9.PubMedPubMedCentralCrossRef
29.
Harada K, Ferdous T, Ueyama Y. Establishment of 5-fluorouracil- resistant oral squamous cell carcinoma cell lines with epithelial to mesenchymal transition changes, vol. 44; 2014.
30.
Andreadis C, Vahtsevanos K, Sidiras T, Thomaidis I, Antoniadis K, Mouratidou D. 5-fluorouracil and cisplatin in the treatment of advanced oral cancer. Oral Oncol. 2003;39(4):380–5.PubMedCrossRef
31.
Lala M, Chirovsky D, Cheng JD, Mayawala K. Clinical outcomes with therapies for previously treated recurrent/metastatic head-and-neck squamous cell carcinoma (R/M HNSCC): a systematic literature review. Oral Oncol. 2018;84:108–20.PubMedCrossRef
32.
Omura K. Current status of oral cancer treatment strategies: Surgical treatments for oral squamous cell carcinoma, vol. 19; 2014.
33.
Christopher AF, Kaur RP, Kaur G, Kaur A, Gupta V, Bansal P. MicroRNA therapeutics: discovering novel targets and developing specific therapy. Perspect Clin Res. 2016;7(2):68–74.PubMedPubMedCentralCrossRef
34.
35.
Zhang Z, Wang C-Z, Du G-J, Qi L-W, Calway T, He T-C, Du W, Yuan C-S. Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells. Int J Oncol. 2013;43(1):289–96.PubMedPubMedCentralCrossRef
36.
Schmidt FK-T, Christiane & Frank, Brigitte & Wolburg, Hartwig & Weller, Michael.: The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines. In: Oncology reports. vol. 19; 2008: 1061–1066.
37.
Yang E-B, Wang D-F, Mack P, Cheng L-Y. Genistein, a tyrosine kinase inhibitor, reduces EGF-induced EGF receptor internalization and degradation in human hepatoma HepG2 cells. Biochem Biophys Res Commun. 1996;224(2):309–17.PubMedCrossRef
38.
Moltzahn FR, Volkmer J-P, Rottke D, Ackermann R. “Cancer stem cells”—lessons from Hercules to fight the hydra. Urol Oncol. 2008;26(6):581–9.PubMedCrossRef
39.
Kas K, Finger E, Grall F, Gu X, Akbarali Y, Boltax J, Weiss A, Oettgen P, Kapeller R, Libermann TA. ESE-3, a novel member of an epithelium-specific Ets transcription factor subfamily, demonstrates different target gene specificity from ESE-1. J Biol Chem. 2000;275(4):2986–98.PubMedCrossRef
40.
Albino D, Longoni N, Curti L, Mello-Grand M, Pinton S, Civenni G, Thalmann G, D'Ambrosio G, Sarti M, Sessa F, et al. ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features. Cancer Res. 2012;72(11):2889–900.PubMedCrossRef
41.
Cheng Z, Guo J, Chen L, Luo N, Yang W, Qu X. Knockdown of EHF inhibited the proliferation, invasion and tumorigenesis of ovarian cancer cells. Mol Carcinog. 2016;55(6):1048–59.PubMedCrossRef
42.
Hu C-T, Wu J-R, Cheng C-C, Wu W-S. The therapeutic targeting of HGF/c-met signaling in hepatocellular carcinoma: alternative approaches. Cancers. 2017;9(6):58.PubMedCentralCrossRef
43.
Scagliotti GV, Novello S, von Pawel J. The emerging role of MET/HGF inhibitors in oncology. Cancer Treat Rev. 2013;39(7):793–801.PubMedCrossRef
44.
45.
Kermorgant S, Parker PJ. Receptor trafficking controls weak signal delivery: a strategy used by c-met for STAT3 nuclear accumulation. J Cell Biol. 2008;182(5):855–63.PubMedPubMedCentralCrossRef
46.
Barrow-McGee R, Kermorgant S. Met endosomal signalling: in the right place, at the right time. Int J Biochem Cell Biol. 2014;49:69–74.PubMedCrossRef
47.
Bianchi-Smiraglia A, Paesante S, Bakin AV. Integrin β5 contributes to the tumorigenic potential of breast cancer cells through Src-FAK and MEK-ERK signaling pathways. Oncogene. 2013;32(25):3049–58.PubMedCrossRef
48.
49.
Mariotti A, Kedeshian PA, Dans M, Curatola AM, Gagnoux-Palacios L, Giancotti FG. EGF-R signaling through Fyn kinase disrupts the function of integrin α6β4 at hemidesmosomes. role in epithelial cell migration and carcinoma invasion. J Cell Biol. 2001;155(3):447–58.PubMedPubMedCentralCrossRef
50.
Yoshiba S, Ito D, Nagumo T, Shirota T, Hatori M, Shintani S. Hypoxia induces resistance to 5-fluorouracil in oral cancer cells via G1 phase cell cycle arrest. Oral Oncol. 2009;45(2):109–15.PubMedCrossRef
51.
Metadata
Title
A novel miR-365-3p/EHF/keratin 16 axis promotes oral squamous cell carcinoma metastasis, cancer stemness and drug resistance via enhancing β5-integrin/c-met signaling pathway
Authors
Wei-Chieh Huang
Te-Hsuan Jang
Shiao-Lin Tung
Tzu-Chen Yen
Shih-Hsuan Chan
Lu-Hai Wang
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Metastasis
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1091-5

Other articles of this Issue 1/2019

Journal of Experimental & Clinical Cancer Research 1/2019 Go to the issue

Research

Pre-metastatic niche triggers SDF-1/CXCR4 axis and promotes organ colonisation by hepatocellular circulating tumour cells via downregulation of Prrx1

Research

Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis

Research

DHRS2 mediates cell growth inhibition induced by Trichothecin in nasopharyngeal carcinoma

Correction

Correction to: Molecular pattern of lncRNAs in hepatocellular carcinoma

Research

SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production

Research

LINC00612 enhances the proliferation and invasion ability of bladder cancer cells as ceRNA by sponging miR-590 to elevate expression of PHF14
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