MAFIP is a tumor suppressor in cervical cancer that inhibits activation of the nuclear factor‐kappa B pathway

Abstract

Cervical cancer is the second most common cancer in women. Inactivation of tumor suppressor genes underlies the transformation and progression of cervical cancer. Previously, we reported MAFIP can inhibit the growth of human cervical cancer HeLa cells. In this study, MAFIP was found to be downregulated in cervical intraepithelial neoplasia tissues. Induced expression of MAFIP in HeLa cells strongly inhibited tumor formation in nude mice, confirming its tumor suppressor activity in vivo. Overexpression of MAFIP inhibited activation of the NF-jB pathway, a commonly active pathway in cancer cells, by preventing the phosphorylation of IKK and IjBa, degradation of IjBa and the nuclear localization of p65. Induction of c-myc, an oncogene controlled by NF-jB, was severely impaired in the cells overexpressing MAFIP. In contrast, knockdown of MAFIP by siRNA activated the NF-jB pathway and promoted cell proliferation. These data suggest MAFIP functions as a tumor suppressor in cervical cancer in part by inhibiting activation of the NF-jB pathway. (Cancer Sci 2011; 102: 2043-2050 C ervical cancer is a malignant neoplasm of the cervix uteri or cervical area. Just behind breast cancer, cervical cancer is the second most frequent cancer among women. Globally, each year, approximately 490 000 new cases are diagnosed and nearly 270 000 women die from the disease. (1) Enormous cancer-related morbidity and mortality impose significance and urgency on the fundamental research of cervical cancer.In the previous few decades, persistent human papillomavirus (HPV) infection and virus-induced transcription have been proven to play a necessary role in cervical carcinogenesis. (2) However, HPV infection alone is not sufficient to drive the transformation and progression. (3) Recurrent genetic alterations, typically inactivation of tumor suppressor genes (TSG), are required for carcinogenesis. (4) For example, downregulation of LMX-1A and ZBRK1 contribute to the invasion and metastasis of tumor. (5,6) A decreased level of CCS-3 helps to prevent apoptosis, (7) and those of DKK3 and NOL7 are involved in the proliferation of tumor cells. (8,9) NF-jB belongs to a family of transcription factors that control the expression of numerous genes, including those encoding cytokines, chemokines, cell adhesion molecules, growth factors, oncogenes and pro-⁄ anti-apoptotic proteins. (10-12) NF-jB is typically a heterodimeric complex consisting of Rel family proteins p65 and p50. The heterodimer is sequestered in the cytoplasm through its association with IjBa, which is known as the inhibitor of NF-jB. Stimulation of cells by pro-inflammatory cytokines, such as tumor necrosis factor-a (TNF-a), results in the phosphorylation of the IjB kinase (IKK) complex, whose catalysis is generally carried out by three tightly associated IKK subunits. IKKa and IKKb serve as the catalytic subunits of the kinase. IJJc(MELO) serves as the regulatory subunit. (13) Ser177 and Ser181 in the activation loop of IKKb (176 and 180 in IKKa) are the specific sites whose phosphory...

Goyazensolide Induces Apoptosis in Cancer Cells in vitro and in vivo

“…Activation of NF-κB through phosphorylation by the IKK complex (IKKα and IKKβ) and subsequent released from IκB in the cytoplasm, occur in the presence of TNFα as an activator, and is known as the canonical NF-κB pathway ( Garg and Aggarwal, 2002 ; Fitzgerald et al ., 2007 ). Inhibition of NF-κB results in apoptosis and suppression of tumor cell growth ( Li et al ., 2011 ; Olivera et al ., 2012 ; Sato et al ., 2011 ; Wilken et al ., 2011 ; Wu et al .,2011 ; Wu and Zhou, 2010 ; Kishida et al ., 2007 ; Oka et al ., 2007 ; Idris et al ., 2009 ; Moon et al ., 2009 ). Thus, this protein complex has been widely used as a key target for new anticancer drug discovery and development ( Garg and Aggarwal, 2002 ) .…”

“…Previous studies have shown that inhibition of NF-κB activation induce apoptosis and suppress tumor growth ( Li et al ., 2011 ; Olivera et al ., 2012 ; Sato et al ., 2011 ; Wilken et al ., 2011. ; Wu and Zhou, 2010 ; Ahmad et al ., 2002 ; Kishida et al ., 2007 ; Oka et al ., 2007 ; Idris et al ., 2009 ; Moon et al ., 2009 ).…”

“…Inhibition of IKKα and IKKβ results in the suppression of NF-κB activation and blocks tumor cell proliferation ( Nakanishi and Toi, 2005 ). Therefore, IKKα, IKKβ, and NF-κB are widely used as molecular targets for the discovery new anticancer drugs ( Li et al ., 2011 ; Wu and Zhou, 2010 ). Recently, several natural products have been reported to exhibit potential antitumor activity through inhibition of NF-κB activation and some are under clinical development, such as parthenolide ( Kishida et al ., 2007 ; Oka et al ., 2007 ; Idris et al ., 2009 ).…”

Polyclonal antibody preparation against candidate tumour suppressor protein MIP for detection of its expression and localization in hepatocellular carcinoma

“…The mRNA expression profile analysis has shown that MIP is expressed in human tissues such as liver, brain, kidney, heart and lung; but it is absent in skeletal muscle and pancreas tissues [2]. Compared with the corresponding normal tissues, the mRNA level of MIP is decreased significantly in some tumours [3]. MIP overexpression inhibits the growth and colony formation of human HCC cell line SMMC7721 [4].…”

“…MIP overexpression inhibits the growth and colony formation of human HCC cell line SMMC7721 [4]. Moreover, exogenous overexpression of MIP in Hela cells can inhibit tumour formation in nude mice [3]. Therefore, MIP is regarded as a candidate tumour suppressor protein.…”