Regulation of CD44v6 expression in gastric carcinoma by the IL-6/STAT3 signaling pathway and its clinical significance
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Yuan-Yuan Xu1, Ming Guo2, Liu-Qing Yang1, Fan Zhou1, Cao Yu1, Aixiu Wang1, Tao-Hong Pang1, Hong-Yan Wu3, Xiao-Ping Zou1, Wei-Jie Zhang4,5, Lei Wang1, Gui-Fang Xu1 and Qin Huang3,6
1Department of Gastroenterology, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
2Department of Gastroenterology, People’s Hospital of Anji, Huzhou, China
3Department of Pathology, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
4Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
5Department of General Surgery, Nanjing Drum Tower Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
6Department of Pathology, VA Boston Healthcare System and Harvard Medical School, Boston, MA, United States
Gui-Fang Xu, email: [email protected]
Lei Wang, email: [email protected]
Wei-Jie Zhang, email: [email protected]
Keywords: CD44v6, cancer stem cell, gastric carcinoma, IL-6, STAT3
Received: November 04, 2016 Accepted: April 11, 2017 Published: April 26, 2017
As a cancer stem cell marker, CD44 variant 6 (CD44v6) has been implicated in carcinogenesis, tumor progression, and metastasis in a variety of human carcinomas. However, little is known about the expression of CD44v6 in Gastric Carcinoma (GC). Therefore we investigated CD44v6 expression in clinical specimen and further explore the underlying molecular mechanisms.
In this study, we systemically investigated CD44v6 expression by immunohistochemistry in normal, premalignant gastric mucosa (low and high grade intraepithelial neoplasia), and GC at various stages. The correlation of CD44v6 expression with clinicopathological characteristics, and prognosis in GC was also analyzed. Next, we investigated cell proliferation, migration and invasion in GC cell lines. Furthermore, we explored a novel mechanism by which CD44V6 was upregulated in GC cell.
The immunohistochemistry results showed that enhanced expression of CD44v6 was closely associated with tumor differentiation, lymph node metastasis, TNM stage and poor prognosis in GC patients. In gastric cancer cell lines, CD44v6 involved in cell proliferation, invasion and metastasis in Next, report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD44v6. RNA interference silencing of STAT3 resulted in decrease of CD44v6 levels. We also found that STAT3 inhibitor AG490 decrease expression of CD44v6 by blocking activation of STAT3, even in the presence of IL-6. Targeting STAT3-mediated CD44v6 up-regulation may represent a novel, effective treatment by eradicating the stomach tumor microenvironment.
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