Abstract
The hyaluronan-mediated motility receptor (HMMR) is overexpressed in gastric cancer; however, the apparent role of HMMR has not been well defined owing to lack of detailed studies on gastric tumorigenesis. Therefore, we elucidated the functional and regulatory mechanisms of HMMR in gastric cancer. Using publicly available data, we confirmed HMMR overexpression in patients with gastric cancer. HMMR silencing decreased proliferation, migration, and invasion of gastric cancer cells, whereas HMMR overexpression reversed these effects. A gastric cancer xenograft mouse model showed statistically significant inhibition of tumor growth upon HMMR depletion. Previous data from cDNA microarray showed reduced HMMR expression upon inhibition of galectin-3. However, overexpression of galectin-3 increased HMMR expression, cell proliferation, and motility in gastric cancer cells, whereas HMMR silencing blocked these effects. Interestingly, galectin-3 interacted directly with C/EBPβ and bound to HMMR promoter to drive its transcription, and gastric cancer cell proliferation and motility. Altogether, high expression of HMMR promoted gastric cancer cell proliferation and motility and could be a prognostic factor in gastric cancer. In addition, HMMR expression was regulated by the interaction between C/EBPβ and galectin-3. Therefore, targeting HMMR along with galectin-3 and C/EBPβ complex could be a potential treatment strategy for inhibiting gastric cancer progression and metastasis. IMPLICATIONS: This study provides evidence that galectin-3 interacts with C/EBPβ in gastric cancer, and galectin-3 and C/EBPβ complex promotes gastric cancer cell progression and motility through upregulating HMMR expression.
Highlights
Gastric cancer is the fourth most common type of cancer and the second leading cause of cancer-related deaths worldwide [1, 2]
hyaluronan-mediated motility receptor (HMMR) expression was high in a majority of patients with gastric cancer, which correlated with their poor survival
HMMR expression levels were determined from gastric cancer patient data, available in the Gene Expression Omnibus (GEO) database (Fig. 1A–C)
Summary
Gastric cancer is the fourth most common type of cancer and the second leading cause of cancer-related deaths worldwide [1, 2]. Despite current developments in diagnosis, as well as surgical and pharmacologic approaches, metastasized gastric cancer leads to poor prognosis and mortality [3,4,5,6,7]. Patients who present with the most favorable characteristics and undergo curative surgical resection often die of recurrent disease due to metastasis [8]. Several recent studies have focused on gastric cancer metastasis [9, 10], the underlying molecular mechanism of this phenomenon has not been completely elucidated [10]. We aimed to understand the underlying processes involved in gastric cancer metastasis, focusing on specific targets to improve gastric cancer prognosis.
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