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      MicroRNA-362 Inhibits Cell Proliferation and Invasion by Directly Targeting SIX1 in Colorectal Cancer

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          Abstract

          Purpose

          Colorectal cancer (CRC) is the third most common cancer in China and poses high morbidity and mortality. In recent years, increasing evidence has indicated that microRNAs played important functions in the occurrence and development of tumors. The purpose of this study was to identify the biological mechanisms of miR-362 in CRC.

          Materials and Methods

          Quantitative real-time PCR was carried out to assess the expression of miR-362 and SIX1. The Kaplan-Meier method was employed to evaluate the 5-year overall survival of CRC patients. The proliferative and invasive abilities of CRC cells were assessed by MTT and transwell assays.

          Results

          miR-362 was significantly decreased in CRC tissues and cell lines, compared to the normal tissues and normal cells. A significant connection was confirmed between the overall survival of 53 CRC patients and low expression of miR-362. Downregulation of miR-362 inhibited the proliferation and invasion through binding to the 3′-UTR of SIX1 mRNA in CRC. Additionally, we discovered that SIX1 was a direct target gene of miR-362 and that the expression of miR-362 had a negative connection with SIX1 expression in CRC. SIX1 could reverse partial functions in the proliferation and invasion in CRC cells.

          Conclusion

          miR-362 may be a prognostic marker in CRC and suppress CRC cell proliferation and invasion in part through targeting the 3′-UTR of SIX1 mRNA. The newly identified miR-362/SIX1 axis provides insight into the progression of CRC.

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          Most cited references31

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          The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease.

          J. Kumar (2009)
          The sine oculis homeobox (SIX) protein family is a group of evolutionarily conserved transcription factors that are found in diverse organisms that range from flatworms to humans. These factors are expressed within, and play pivotal developmental roles in, cell populations that give rise to the head, retina, ear, nose, brain, kidney, muscle and gonads. Mutations within the fly and mammalian versions of these genes have adverse consequences on the development of these organs/tissues. Several SIX proteins have been shown to directly influence the cell cycle and are present at elevated levels during tumorigenesis and within several cancers. This review aims to highlight aspects of (1) the evolutionary history of the SIX family; (2) the structural differences and similarities amongst the different SIX proteins; (3) the role that these genes play in retinal development; and (4) the influence that these proteins have on cell proliferation and growth.
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            The six family of homeobox genes in development and cancer.

            The homeobox gene superfamily encodes transcription factors that act as master regulators of development through their ability to activate or repress a diverse range of downstream target genes. Numerous families exist within the homeobox gene superfamily, and are classified on the basis of conservation of their homeodomains as well as additional motifs that contribute to DNA binding and to interactions with other proteins. Members of one such family, the Six family, form a transcriptional complex with Eya and Dach proteins, and together these proteins make up part of the retinal determination network first identified in Drosophila. This network is highly conserved in both invertebrate and vertebrate species, where it influences the development of numerous organs in addition to the eye, primarily through regulation of cell proliferation, survival, migration, and invasion. Mutations in Six, Eya, and Dach genes have been identified in a variety of human genetic disorders, demonstrating their critical role in human development. In addition, aberrant expression of Six, Eya, and Dach occurs in numerous human tumors, and Six1, in particular, plays a causal role both in tumor initiation and in metastasis. Emerging evidence for the importance of Six family members and their cofactors in numerous human tumors suggests that targeting of this complex may be a novel and powerful means to inhibit both tumor growth and progression.
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              Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth.

              The Six1 homeodomain protein is a developmental transcription factor that has been implicated in tumor onset and progression. Our recent work shows that Six1 overexpression in human breast cancer cell lines is sufficient to induce epithelial-to-mesenchymal transition (EMT) and metastasis. Importantly, Six1-induced EMT and metastasis are dependent on TGF-β signaling. The TGF-β pathway plays a dual role in cancer, acting as a tumor suppressor in early lesions but enhancing metastatic spread in more advanced tumors. Our previous work indicated that Six1 may be a critical mediator of the switch in TGF-β signaling from tumor suppressive to tumor promotional. However, the mechanism by which Six1 impinges on the TGF-β pathway was, until now, unclear. In this work, we identify the TGF-β type I receptor (TβRI) as a target of Six1 and a critical effector of Six1-induced TGF-β signaling and EMT. We show that Six1-induced upregulation of TβRI is both necessary and sufficient to activate TGF-β signaling and induce properties of EMT. Interestingly, increased TβRI expression is not sufficient to induce experimental metastasis, providing in vivo evidence that Six1 overexpression is required to switch TGF-β signaling to the prometastatic phenotype and showing that induction of EMT is not sufficient to induce experimental metastasis. Together, these results show a novel mechanism for the activation of TGF-β signaling, identify TβRI as a new target of Six1, and implicate Six1 as a determinant of TGF-β function in breast cancer. ©2010 AACR.
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                Author and article information

                Journal
                Yonsei Med J
                Yonsei Med. J
                YMJ
                Yonsei Medical Journal
                Yonsei University College of Medicine
                0513-5796
                1976-2437
                01 May 2019
                19 April 2019
                : 60
                : 5
                : 414-422
                Affiliations
                [1 ]Department of Hyperbaric Oxygen, The Affiliated Hospital of Qingdao University, Qingdao, China.
                [2 ]Department of Oncology, Zouping Centre Hospital, Binzhou, China.
                [3 ]Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
                Author notes
                Corresponding author: Gang Zhao, MD, Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, No.1677 Wutaishan Road, Huangdao District, Qingdao 266000, Shandong, China. Tel: 86-0532-82919561, Fax: 86-0532-82919561, ttrsog32694329@ 123456163.com
                Author information
                https://orcid.org/0000-0002-5196-2344
                https://orcid.org/0000-0001-5772-151X
                https://orcid.org/0000-0002-7406-6542
                https://orcid.org/0000-0002-8590-7466
                https://orcid.org/0000-0002-2462-6927
                https://orcid.org/0000-0002-8406-8656
                https://orcid.org/0000-0002-3628-9569
                https://orcid.org/0000-0002-2315-2045
                Article
                10.3349/ymj.2019.60.5.414
                6479121
                31016902
                f5ff302b-5a9d-4f04-af94-e46cdae701a4
                © Copyright: Yonsei University College of Medicine 2019

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 January 2019
                : 27 February 2019
                : 07 March 2019
                Categories
                Original Article
                Oncology

                Medicine
                mir-362,six,proliferation,invasion,colorectal cancer
                Medicine
                mir-362, six, proliferation, invasion, colorectal cancer

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