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31.01.2019 | Gastrointestinal Oncology

Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer

verfasst von: Toshimichi Tanaka, MD, Keita Kojima, MD, PhD, Kazuko Yokota, MD, Yoko Tanaka, MD, Yosuke Ooizumi, MD, Satoru Ishii, MD, PhD, Nobuyuki Nishizawa, MD, PhD, Keigo Yokoi, MD, PhD, Hideki Ushiku, MD, PhD, Mariko Kikuchi, MD, PhD, Ken Kojo, MD, PhD, Naoko Minatani, MD, PhD, Hiroshi Katoh, MD, PhD, Takeo Sato, MD, PhD, Takatoshi Nakamura, MD, PhD, Masakazu Sawanobori, MD, PhD, Masahiko Watanabe, MD, PhD, FACS, Keishi Yamashita, MD, PhD, FACS

Erschienen in: Annals of Surgical Oncology | Ausgabe 5/2019

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Abstract

Background

Treatment-resistance genes limiting anticancer therapy have not been well clarified in colorectal cancer (CRC). We explored gene expression profiles to identify biomarkers for predicting treatment resistance to an anticancer drug in CRC.

Methods

Six CRC cell lines were treated with phenylbutyrate (PB). The gene expression profiles were then compared using microarrays (harboring 54,675 genes), and genes associated with PB resistance were identified. Candidate genes were functionally examined in cell lines and clinically validated for treatment resistance in clinical samples.

Results

Both DLD1 and HCT15 cells were PB resistant, while HCT116 cells were identified as PB sensitive. On microarray analysis, among the PB resistance-related genes, the expression of the genes ASCL2, LEF1, and TSPAN8 was clearly associated with PB resistance. PB-sensitive cells transfected with one of these three genes exhibited significant (P < 0.001) augmentation of PB resistance; ASCL2 induced expression of both LEF1 and TSPAN8, while neither LEF1 nor TSPAN8 induced ASCL2. RNA interference via ASCL2 knockdown made PB-resistant cells sensitive to PB and inhibited both genes. ASCL2 knockdown also played a critical role in sensitivity to treatment by 5-fluorouracil and radiotherapy in addition to PB. Finally, ASCL2 expression was significantly correlated with histological grade of rectal cancer with preoperative chemoradiation therapy.

Conclusions

ASCL2 was identified as a causative gene involved in therapeutic resistance against anticancer treatments in CRC.

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Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 371:1007–16CrossRefPubMedPubMedCentral

Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 25:1346–55CrossRefPubMed

Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 15:1065–75CrossRefPubMed

Nakamura T, Yamashita K, Sato T, et al. Neoadjuvant chemoradiation therapy using concurrent S-1 and irinotecan in rectal cancer: impact on long-term clinical outcomes and prognostic factors. Int J Radiat Oncol Biol Phys. 2014 89:547–55CrossRefPubMed

Yamada Y, Takahari D, Matsumoto H, et al. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 14:1278–86CrossRefPubMed

Kikuchi M, Yamashita K, Waraya M, et al. Epigenetic regulation of ZEB1-RAB25/ESRP1 axis plays a critical role in phenylbutyrate treatment-resistant breast cancer. Oncotarget. 2016 7:1741–53CrossRefPubMed

Zhang P, Sun Y, Ma L. ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle. 2015 14:481–7CrossRefPubMedPubMedCentral

Viswanathan VS, Ryan MJ, Dhruv HD, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017 547:453–457CrossRefPubMedPubMedCentral

Katoh H, Yamashita K, Waraya M, et al. Epigenetic silencing of HOPX promotes cancer progression in colorectal cancer. Neoplasia. 2012 14:559–71CrossRefPubMedPubMedCentral

10.

Gilbert J, Baker SD, Bowling MK, et al. A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res. 2001 7:2292–300PubMed

11.

Jubb AM, Chalasani S, Frantz GD, et al. Achaete-scute like 2 (ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia. Oncogene. 2006 25:3445–57CrossRefPubMed

12.

Nakayama N, Yamashita K, Tanaka T, et al. Genomic gain of the PRL-3 gene may represent poor prognosis of primary colorectal cancer, and associate with liver metastasis. Clin Exp Metastasis. 2016 33:3–13CrossRefPubMed

13.

Ooki A, Yamashita K, Kikuchi S, et al. Phosphatase of regenerating liver-3 as a convergent therapeutic target for lymph node metastasis in esophageal squamous cell carcinoma. Int J Cancer. 2010 127:543–54CrossRefPubMed

14.

van der Flier LG, van Gijn ME, Hatzis P, et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell. 2009 136:903–12CrossRefPubMed

15.

Yamashita K, Upadhyay S, Osada M, et al. Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell. 2002 2:485–95CrossRefPubMed

16.

Mellor HR, Harris AL. The role of the hypoxia-inducible BH3-only proteins BNIP3 and BNIP3L in cancer. Cancer Metastasis Rev. 2007 26:553–66CrossRefPubMed

17.

Li L, Yang D, Cui D, et al. Quantitative proteomics analysis of the role of tetraspanin-8 in the drug resistance of gastric cancer. Int J Oncol. 2018 52:473–484PubMed

18.

Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007 318:1108–13CrossRefPubMed

19.

Stange DE, Engel F, Longerich T, et al. Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain. Gut. 2010 59:1236–44

20.

Sato T, Ozawa H, Hatate K, et al. A Phase II trial of neoadjuvant preoperative chemoradiotherapy with S-1 plus irinotecan and radiation in patients with locally advanced rectal cancer: clinical feasibility and response rate. Int J Radiat Oncol Biol Phys. 2011 79:677–83CrossRefPubMed

21.

Pieraccioli M, Imbastari F, Antonov A, et al. Activation of miR200 by c-Myb depends on ZEB1 expression and miR200 promoter methylation. Cell Cycle. 2013 12:2309–20CrossRefPubMedPubMedCentral

22.

Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006 127:469–80CrossRefPubMed

23.

Bai J, Sui J, Demirjian A, et al. Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro. Cancer Res. 2005 65:2344–52CrossRefPubMed

24.

Wang L, Xue M, Chung DC. c-Myc is regulated by HIF-2alpha in chronic hypoxia and influences sensitivity to 5-FU in colon cancer. Oncotarget. 2016 7:78910–78917PubMedPubMedCentral

25.

Kuhn S, Koch M, Nubel T, et al. A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. Mol Cancer Res. 2007 5:553–67CrossRefPubMed

26.

Ishii S, Yamashita K, Harada H, et al. The H19-PEG10/IGF2BP3 axis promotes gastric cancer progression in patients with high lymph node ratios. Oncotarget. 2017 8:74567–74581PubMedPubMedCentral

27.

Pan SJ, Wu YB, Cai S, et al. Over-expression of tetraspanin 8 in malignant glioma regulates tumor cell progression. Biochem Biophys Res Commun. 2015 458:476–482CrossRefPubMed

28.

Yue S, Mu W, Erb U, et al. The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding. Oncotarget. 2015 6:2366–84PubMed

29.

Fu NY, Rios AC, Pal B, et al. Identification of quiescent and spatially restricted mammary stem cells that are hormone responsive. Nat Cell Biol. 2017 19:164–176CrossRefPubMed

30.

Cajigas-Du Ross CK, Martinez SR, Woods-Burnham L, et al. RNA sequencing reveals upregulation of a transcriptomic program associated with stemness in metastatic prostate cancer cells selected for taxane resistance. Oncotarget. 2018 9:30363–30384PubMedPubMedCentral

31.

Itzkovitz S, Lyubimova A, Blat IC, et al. Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat Cell Biol. 2011 14:106–14CrossRefPubMedPubMedCentral

32.

Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012 487:330–7

33.

Yamashita K, Katoh H, Watanabe M. The homeobox only protein homeobox (HOPX) and colorectal cancer. Int J Mol Sci. 2013 14:23231–43CrossRefPubMedPubMedCentral

34.

Zhou J, Chang M, Li J, et al. Knockdown of annexin A5 restores gefitinib sensitivity by promoting G2/M cell cycle arrest. Respir Res. 2018 19:96CrossRefPubMedPubMedCentral

35.

Arcy ND, Gabrielli B. Topoisomerase II inhibitors and poisons, and the influence of cell cycle checkpoints. Curr Med Chem. 2017 24:1504–1519

36.

Rakitina TV, Vasilevskaya IA, O’Dwyer PJ. Inhibition of G1/S transition potentiates oxaliplatin-induced cell death in colon cancer cell lines. Biochem Pharmacol. 2007 73:1715–26CrossRefPubMed

37.

Giakountis A, Moulos P, Zarkou V, et al. A positive regulatory loop between a Wnt-regulated non-coding RNA and ASCL2 controls intestinal stem cell fate. Cell Rep. 2016 15:2588–96CrossRefPubMed

Titel: Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer
verfasst von: Toshimichi Tanaka, MD
Keita Kojima, MD, PhD
Kazuko Yokota, MD
Yoko Tanaka, MD
Yosuke Ooizumi, MD
Satoru Ishii, MD, PhD
Nobuyuki Nishizawa, MD, PhD
Keigo Yokoi, MD, PhD
Hideki Ushiku, MD, PhD
Mariko Kikuchi, MD, PhD
Ken Kojo, MD, PhD
Naoko Minatani, MD, PhD
Hiroshi Katoh, MD, PhD
Takeo Sato, MD, PhD
Takatoshi Nakamura, MD, PhD
Masakazu Sawanobori, MD, PhD
Masahiko Watanabe, MD, PhD, FACS
Keishi Yamashita, MD, PhD, FACS
Publikationsdatum: 31.01.2019
Verlag: Springer International Publishing
Erschienen in: Annals of Surgical Oncology / Ausgabe 5/2019
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-019-07172-7

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