Supplementary Tables S1-S4 from Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

Hijiya, Naoki; Tsukamoto, Yoshiyuki; Nakada, Chisato; Tung Nguyen, Lam; Kai, Tomoki; Matsuura, Keiko; Shibata, Kohei; Inomata, Masafumi; Uchida, Tomohisa; Tokunaga, Akinori; Amada, Kohei; Shirao, Kuniaki; Yamada, Yasunari; Mori, Hiromu; Takeuchi, Ichiro; Seto, Masao; Aoki, Masahiro; Takekawa, Mutsuhiro; Moriyama, Masatsugu

doi:10.1158/0008-5472.22411743.v1

00085472can151846-sup-150299_2_supp_3346028_927x8h.docx (38.77 kB)

Supplementary Tables S1-S4 from Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

journal contribution

posted on 2023-03-31, 00:10 authored by Naoki Hijiya, Yoshiyuki Tsukamoto, Chisato Nakada, Lam Tung Nguyen, Tomoki Kai, Keiko Matsuura, Kohei Shibata, Masafumi Inomata, Tomohisa Uchida, Akinori Tokunaga, Kohei Amada, Kuniaki Shirao, Yasunari Yamada, Hiromu Mori, Ichiro Takeuchi, Masao Seto, Masahiro Aoki, Mutsuhiro Takekawa, Masatsugu Moriyama

Clinicopathologic characteristics of 10 cases of IPMN-inv (S1); Chromosomal imbalances frequently detected in IPMN-inv (S2); Clinicopathologic characteristics of 19 cases of IDC (S3); Comparison of frequent chromosomal aberrations in IDC with those in the invasive region of IPMN-inv (S4).

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Japan Society for the Promotion of Science

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ARTICLE ABSTRACT

The progression from precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN), to invasive disease is characterized by stepwise accumulation of genetic alterations. However, it remains unclear whether additional alterations are required for the progression of high-grade neoplasms to invasive pancreatic carcinoma. We compared the genomic profiles of paired noninvasive and invasive carcinoma tissues collected from patients with IPMN. We demonstrate that the frequency of genomic copy-number aberrations significantly increased during the course of invasion, and the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, an MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter as well as in invasive carcinomas due to genomic loss. Restoration of DUSP4 expression in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival. Collectively, our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling. Cancer Res; 76(9); 2612–25. ©2016 AACR.

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Carcinogenesis Premalignancy Tumor initiation and promotion Cell Signaling Phosphatases Gastrointestinal Cancers Pancreatic cancer Oncogenes & Tumor Suppressors Tumor suppressor genes Progression, Invasion & Metastasis Migration and invasion Tumor progression

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Supplementary Tables S1-S4 from Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

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Japan Society for the Promotion of Science

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ARTICLE ABSTRACT

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