MicroRNA-143 functions as a tumor suppressor in human esophageal squamous cell carcinoma
Highlights
► miR-143 and miR-145 expression levels are analyzed in ESCC. ► miR-143 low expression is associated with lymph node metastasis and invasion depth. ► miR-143 inhibits cell migration and invasion in ESCC cells in vitro. ► miR-143 induces apoptosis in ESCC cells. ► miR-143 suppresses the expression of ERK5 protein in esophageal cancer.
Introduction
Esophageal cancer is one of the most common cancers worldwide with a variable geographic distribution and ranks eighth in order of occurrence and is the sixth leading cause of cancer mortality, affecting men more than women (Enzinger and Mayer, 2003). It has two main forms, esophageal squamous cell carcinoma (ESCC) and adenocarcinoma, each with distinct etiologic and pathologic characteristics. At present ESCC is the most predominant form worldwide, adenocarcinoma of the esophagus though is increasing at an alarming rate in Western Europe and the United States (Blot and McLaughlin, 1999). Because most cases of ESCC are diagnosed at an advanced stage, the prognosis for patients is poor despite the development of therapeutic options such as surgery, chemotherapy and radiotherapy. Research over the last two decades has identified a variety of oncogenic and tumor-suppressor proteins which are associated with the induction of ESCC (Gratas et al., 1998, Hollstein et al., 1990, Hu et al., 2004, Jiang et al., 1993, Mizushima et al., 2002, Shih et al., 2000). However, to date, efforts to identify accurate molecules that regulate the initiation and progression of ESCC have elucidated only a few molecular mechanisms.
MicroRNAs(miRNAs) are a class of naturally occurring small (21–25 nucleotides) noncoding RNAs which can block the translation of specific messenger RNA by binding through complementary target sequences of the mRNAs (Alvarez-Garcia and Miska, 2005, Bartel, 2004, Croce and Calin, 2005, McManus, 2003, Mendell, 2005). Mature miRNAs play important regulatory roles in processes such as differentiation, proliferation, and apoptosis (Ambros, 2004, Chen et al., 2004). Furthermore, some miRNAs may function either as oncogenes or tumor suppressors. Specifically, miRNA-143 and miRNA-145, which are transcribed as the same primary miR at chromosome 5q33, are often down-regulated in colon, gastric and other cancers (Akao et al., 2006, Akao et al., 2007b, Takagi et al., 2009, Tong et al., 2009, Wang et al., 2008). Previous studies showed that the 5q was one of the most common region of loss in ESCC, which predicts that it may harbor novel tumor suppressor genes (Chang et al., 2010, Hu et al., 2000, Moskaluk et al., 1998, Pack et al., 1999). Furthermore, miRNA-143 was idetified as a putative cancer suppressor in bladder cancer (Lin et al., 2009), colorectal cancer (Zhang et al., 2012) and B-cell malignancies (Akao et al., 2007a). In addition, miRNA-143 has been found to directly target multiple mRNAs of KRAS (Chen et al., 2009, Suzuki et al., 2009), ELK1 (Cordes et al., 2009), MYO6 (Szczyrba et al., 2010), Bcl-2 (Zhang et al., 2010) and ERK5 (Akao et al., 2009), which then are involved in the pathogenesis of cancers.
However, the expression levels and functions of miRNA-143 and miRNA-145 in ESCC tissue and cells are still under debate (Akagi et al., 2011, Kano et al., 2010), indicating that they may play diverse roles in the carcinogenesis of ESCC. Moreover, the impact of miRNA-143 to its most widely reported direct targets-RAS, Bcl-2 and ERK5 in ESCC is still unknown. In the present study, we confirmed the decreased expression levels of miRNA-143 in ESCC patients tissue samples as well as ESCC cell lines. Our results provided evidences that miRNA-143 overexpression could markedly reduce human esophageal cancer cell growth in vitro, causing increased tumor cell apoptosis and decreased proliferation. In addition, miRNA-143 overexpression significantly inhibited ESCC cells invasion and migration with a marked decrease in ERK5 levels but relatively stable RAS and Bcl-2 levels.
Section snippets
Specimens and cell culture
40 pairs of primary esophageal squamous cell carcinoma and corresponding normal esophageal epitheliums were obtained from patients in the Provincial Hospital Affiliated to Shandong University from 2010 to 2011 with informed consent. All tissue samples were from untreated patients undergoing surgery and all clinicopathologic information was available. The study was approved by the Hospitals' Ethical Review Committee. The specimens were snap frozen in liquid nitrogen.
Human esophageal squamous
Down regulation of miR-143,145 expression in ESCC
To investigate the role of miR-143,145 in esophagus malignancies, we first evaluated the expression levels of miR-143,145 in clinical samples of ESCCs and matched NESTs by TaqMan real-time PCR (p < 0.01, Figs. 1A;B). Expression of U6 small RNA was used as an internal standard. Compared with NEST, a significant downregulation of miR-143 and miR-145 expressions in ESCC was noted. The mean levels of miR-143 and miR-145 in ESCC were decreased about 51.6% and 58.4% of that in NEST, respectively (p <
Discussion
It was known that miRNAs have emerged as important regulators of protein post-transcriptional regulation. Accumulated evidence has indicated that several miRNAs can act as tumor suppressors depending on the targeting of specific oncogenes, and the aberrant expression of tumor supressive miRNAs may contribute to human carcinogenesis (Calin et al., 2002, Zhang et al., 2007, Zhu et al., 2008). MiR-143 is localized at 5q32-33 and down-regulated in various human malignancies including colorectal
Acknowledgments
This work was supported by grants from the Natural Science Foundation of Shandong Province of China (ZR2010HM067 and ZR2011HM077), and the Science and Technology Development Planning of Shandong of China (2011GGH21819).
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These authors contributed equally to this work.