Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer

Abstract

We identified IFIX as a new member of the hematopoietic interferon (IFN)-inducible nuclear protein with the 200-amino-acid repeat (HIN-200) family. Six different alternatively spliced forms of mRNA are transcribed from the IFIX gene, which are predicted to encode six different isoforms of IFIX proteins (IFIXa1, a2, b1, b2, c1, and c2). The IFIX proteins are primarily localized in the nucleus. They share a common N-terminal region that contains a predicted pyrin domain and a putative nuclear localization signal. Unlike IFIXa and IFIXb, IFIXc isoforms do not have the 200-amino-acid signature motif. Interestingly, the expression of IFIX was reduced in most human breast tumors and breast cancer cell lines. Expression of IFIXa1, the longest isoform of IFIX, in human breast cancer cell lines reduced their anchoragedependent and -independent growth in vitro and tumorigenicity in nude mice. Moreover, a liposome-mediated IFIXa1 gene transfer suppressed the growth of alreadyformed tumors in a breast cancer xenograft model. IFIXa1 appears to suppress the growth of breast cancer cells in a pRB-and p53-independent manner by increasing the expression of the cyclin-dependent kinase inhibitor p21 CIP1 , which leads to the reduction of the kinase activity of both Cdk2 and p34 Cdc2. Together, our results show that IFIXa1 possesses a tumor-suppressor activity and suggest IFIXa1 may be used as a therapeutic agent in cancer treatment.

The emerging role of human PYHIN proteins in innate immunity: Implications for health and disease

“…In addition, isoforms a1, a2, b1 and b2 contain a HIN domain which is absent in both the g1, and g2 isoforms [6]. Like the PYD of other nuclear expressed PYHIN proteins, that of PYHIN1 also appears to form aggregates when expressed alone [29].…”

“…Functionally, roles for PYHIN1 in cell growth and tumour suppression have been reported. PYHIN1 expression has been reported to be reduced in breast tumours and breast cancer cell lines [6]. It is believed that PYHIN1a1 possesses tumour suppressive activity mediated by its ability to interact with and destabilise the oncoprotein HDM2.…”

“…This results in p53 stabilisation and activation of p53 responsive genes, such as the cyclin dependent kinase inhibitor p21CIP1. Consequently, CDK2 kinase activity is reduced and cell growth is inhibited [6,31]. A functional link between PYHIN1a and maspin has also been proposed.…”

AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model

“…The human IFN-inducible protein IFIXa1 has been shown to reduce the anchorage-dependent and anchorageindependent growth and the tumorigenicity of breast cancer cells (14). Another human IFN-inducible protein that may associate with tumor suppression activity is AIM2.…”

“…Another human IFN-inducible protein that may associate with tumor suppression activity is AIM2. AIM2 gene was originally identified by subtractive cDNA selection for association with human melanoma tumorigenicity (15) and only shares 31% protein identity with IFIXa1 (14). The AIM2 gene contains a site of microsatellite instability that results in gene inactivation in 47.6% of colorectal tumors with high microsatellite instability (16).…”