Abstract
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.
Highlights
Gastric carcinoma (GC) is the fourth most common malignancy and the third leading cause of cancer-related death world-wide [1, 2]
Expression of CD44 is expressed as a standard form (CD44s) variant 6 (CD44v6) and pSTAT3 were significantly elevated in different stages of GC, as shown in Figure 1A, B and Supplementary Table 1
It is well established that the tumor cancer stem cells (CSCs) surface marker, CD44v6, is causally involved in cancer metastasis [29], correlated with tumorigenesis in some cancer types
Summary
Gastric carcinoma (GC) is the fourth most common malignancy and the third leading cause of cancer-related death world-wide [1, 2]. Tumor recurrence including metastasis is the main cause of cancer-related death. Tumor recurrence after radical gastrectomy with curative intent is relatively common, occurring in 20% to 50% of GC patients [4, 5]. Because CSCs possess the ability to initiate tumorigenesis, promote progression, and resist conventional chemotherapies [8, 10, 11], the concept that CSCs are responsible for tumor initiation is quite well established. The role of CSCs in tumor recurrence remains poorly understood, especially in GC [12, 13]
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