Abstract
Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the development and progression of many tumors. In this study, XIST was specifically upregulated in pancreatic carcinoma tissues and cell lines; a higher XIST expression was correlated to poorer clinicopathologic features. After XIST knockdown, the proliferation of PC cell lines was suppressed and cell cycle stagnated in G1 phase; XIST knockdown also reduced the protein levels of inhibitor of apoptosis-stimulating protein of p53 (iASPP) and Cyclin-dependent kinase 1 (CDK1), increased the protein level of P21, a potent CDK inhibitor. In PC cell lines, XIST and miR-140/miR-124, two tumor-associated miRNAs, could inversely regulate each other, respectively; miR-140/miR-124 could bind to XIST and the 3’UTR of PPP1R13L, respectively. XIST and miR-140/miR-124 exerted opposite effects on iASPP, CDK1, P21 and P27 proteins; whereas the effects of LV-sh-XIST on the indicated protein levels could be partially reversed by miR-140 and/or miR-124 inhibitor. In PC tissues, miR-140 and miR-124 expression was down-regulated, iASPP and CDK1 mRNA expression was up-regulated. XIST positively correlated with iASPP and CDK1, inversely correlated with miR-140 and miR-124, respectively. Taken together, our data indicated that XIST might be an oncogenic lncRNA that promoted proliferation of PC cell line through inhibiting miR-140/miR-124 expression and promoting cell cycle-related factor expression, and could be regarded as a therapeutic target in human pancreatic carcinoma.
Highlights
Pancreatic adenocarcinoma is a highly malignant phenotype characterized by rapid progression, early metastasis, and a limited response to radiotherapy and chemotherapy
X-inactive specific transcript (XIST) expression was upregulated in PC tissues of I+II, III or IV TNM stage, compared with normal tissues (Figure 1C). 73 cases of PC tissues were divided into two groups: a high XIST expression group and a low XIST expression group
The results indicated that patients with higher XIST expression had a significantly shorter OS (P=0.003) and DFS (P=0.002) compared to patients with lower XIST expression (Figure 1D and 1E)
Summary
Pancreatic adenocarcinoma is a highly malignant phenotype characterized by rapid progression, early metastasis, and a limited response to radiotherapy and chemotherapy. Progress in the treatment of PC depends to a great extent on an increased understanding of the underlying molecular mechanisms and the development of innovation clinical approaches. Small non-coding RNAs such as microRNAs have been studied extensively and their roles in gene regulation and cell function have been elucidated innumerous cancers [4]. Recent studies have shown that lncRNAs play important roles in both normal development and diseases including cancer [5]. LncRNAs have emerged as new players in cancer research and several studies have shown that some lncRNAs function as oncogenes, tumor suppressor genes or both, depending on the circumstance [6]. In the discovered lncRNAs, X-inactive specific transcript (XIST) is involved in the development and progression of many tumors. XIST expression has www.impactjournals.com/oncotarget been found to be dysregulated in a variety of human cancers when compared to normal cells; the dysregulation of XIST expression can affect cancer cell proliferation, invasion and migration [7]
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