Abstract
The long non-coding RNA H19 is highly expressed in several cancers, and the functions of H19 vary among cancer cell types. Recently, we reported that H19 contributes to the metastasis of pancreatic ductal adenocarcinoma (PDAC) cells and that inhibition of H19 reduces metastasis in vivo. However, the molecular mechanisms underlying the metastasis-promoting role of H19 in PDAC cells remain poorly elucidated. In this study, we clarified the mechanisms by which H19 regulates PDAC metastasis, with a focus on cancer stem cells (CSCs), by using H19-overexpressing and knockdown PDAC cells. Whereas the sphere-formation and invasion abilities of PDAC cells depended on H19 expression levels, other CSC characteristics of the cells, including stemness-marker expression and anticancer-drug resistance, were unaffected by H19 levels. Furthermore, metalloproteinase activity, a key mediator of invasion, was also independent of H19 expression. By contrast, H19 promoted cell adhesion through regulation of integrin and CD24 expression. Notably, the increased adhesion of H19-overexpressing cells was blocked by an anti-β1-integrin antibody, and this resulted in the inhibition of sphere formation and invasion. Thus, H19 plays critical roles in the CSC self-renewal and cell adhesion of PDAC that lead to invasion and metastasis. Our findings suggest that H19 represents a novel therapeutic target for the metastasis of pancreatic cancer.
Highlights
Pancreatic cancer is challenging to diagnose at an early stage and is highly metastatic; the overall survival rate for patients with pancreatic cancer is only ~8%
At 7 days after sphere formation under 3D-culture conditions, higher H19 expression was detected among the sphere cells than in cells cultured under the adherent-culture condition (Figure 1B)
These results suggest that H19 is expressed in cancer stem cell (CSC)-like cells among PANC-1 cells
Summary
Pancreatic cancer is challenging to diagnose at an early stage and is highly metastatic; the overall survival rate for patients with pancreatic cancer is only ~8%. Pancreatic cancer is currently the fourthleading and third-leading cause of cancer death in Japan and USA, respectively [1, 2]. Most pancreatic cancer patients are aged >60 years old, and the aging population is rapidly increasing worldwide. By 2030, pancreatic cancer is expected to become the second-leading cause of cancer-related deaths in USA [3]. Even after surgery, the 5-year survival rate is only 15%–20%, because of the high metastatic rate and local recurrence of the cancer [4]. Chemotherapies or chemoradiotherapies can reduce tumor size and improve prognosis, but these treatments do not eliminate all PDAC cells in the patients. Understanding the molecular mechanisms of PDAC carcinogenesis and metastasis could facilitate the identification of potential tumor biomarkers and the development of effective therapeutic strategies against metastasis and recurrence
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