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ARPP-19 Mediates Herceptin Resistance via Regulation of CD44 in Gastric Cancer

Authors Gao X, Lu C, Chen C, Sun K, Liang Q, Shuai J, Wang X, Xu Y

Received 13 March 2020

Accepted for publication 18 June 2020

Published 7 July 2020 Volume 2020:13 Pages 6629—6643

DOI https://doi.org/10.2147/OTT.S253841

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr William Cho


Xiang Gao,1,* Changwen Lu,1,* Changyu Chen,2 Kang Sun,1 Qixin Liang,1 Jianfeng Shuai,1 Xiaoming Wang,1 Yuxing Xu1

1Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, People’s Republic of China; 2Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yuxing Xu
Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, 117 Meishan Avenue, Hefei 230031, Anhui, People’s Republic of China
Tel +86 138-5699-6478
Email blackbird007@163.com

Purpose: As the first-line drug for treatment of HER2-positive metastatic gastric cancer (GC), Herceptin exhibits significant therapeutic efficacy. However, acquired resistance of Herceptin limits the therapeutic benefit of gastric cancer patients, in which the molecular mechanisms remain to be further determined.
Methods: Quantitative real-time polymerase chain reaction was performed to detect the mRNA levels of ARPP-19 and CD44 in GC cells. Protein levels were determined using Western blot and IHC staining. MTT and soft agar colony formation assays were used to measure cell proliferation. Xenograft model was established to verify the functional role of ARPP-19 in Herceptin resistance in vivo. Sphere formation assay was conducted to determine cell stemness.
Results: We observed ARPP-19 was up-regulated in Herceptin resistance gastric cancer cells NCI-N87-HR and MKN45-HR. The forced expression of ARPP-19 promoted, whereas the silencing of ARPP-19 impaired Herceptin resistance of HER2-positive gastric cancer cells both in vitro and in vivo. Moreover, ARPP-19 significantly enhanced the sphere formation capacity and CD44 expression, CD44 was also a positive factor of Herceptin resistance in HER2-positive gastric cancer cells. In addition, high level of ARPP-19 was positively associated with Herceptin resistance and poor survival rate of gastric cancer patients.
Conclusion: We have demonstrated that ARPP-19 promoted Herceptin resistance of gastric cancer via up-regulation of CD44, our study suggested that ARPP-19 could be a potential diagnostic and therapeutic candidate for HER2-positive gastric cancer.

Keywords: Herceptin resistance, HER2, gastric cancer, ARPP-19, CD44

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