Article

Sperm-Associated Antigen 9 Is a Novel Biomarker for Colorectal Cancer and Is Involved in Tumor Growth and Tumorigenicity

Cancer Microarray, Genes and Proteins Laboratory, National Institute of Immunology, New Delhi, India.
American Journal Of Pathology (Impact Factor: 4.59). 03/2011; 178(3):1009-20. DOI: 10.1016/j.ajpath.2010.11.047
Source: PubMed

ABSTRACT

Colorectal cancer (CRC) is the second most common tumor in developed countries. The present study was undertaken to determine the expression of the sperm-associated antigen 9 gene (SPAG9) as a possible biomarker in CRC, to investigate its correlation with humoral immune response and different stages and grades in CRC patients, and to explore its possible role in colon tumorigenesis in vitro and in an in vivo mouse model. SPAG9 expression was determined by RT-PCR, in situ RNA hybridization, and immunohistochemistry. Humoral response against SPAG9 was detected by enzyme-linked immunosorbent assay and Western blotting. SPAG9 gene silencing was performed using plasmid-based small interfering RNA to study various malignant properties of colon cancer cells in vitro and in vivo. The majority of CRC patients showed SPAG9 expression and generated humoral response. There was a close relationship between SPAG9 protein expression and humoral immune response in the majority of early-stage CRC patients, indicating that anti-SPAG9 antibodies could be a novel serum biomarker for early diagnosis. The down-regulation of SPAG9 (mediated by small interfering RNA) inhibited malignant properties in in vitro and significantly suppressed tumor growth in vivo. These findings collectively suggest that SPAG9 may have a role in tumor development and early spread and thus could serve as a novel target for early detection and for cancer immunotherapy.

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    • "in the JNK-signaling module and play an important regulatory role in several physiologic and pathological processes, including cell survival, proliferation , apoptosis, and tumor development232425. Previous studies have shown that the expression of SPAG9 was elevated in a variety of malignancies and correlated with tumor stage and prognosis, including HCC4567811]. At present, the role of aberrant-expressed SPAG9 in tumor development has been partly understood, while overexpressed SPAG9 may induce the activation of JNK signaling leading to tumor progression[4]. "
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    ABSTRACT: Background: The aberrant expression of sperm-associated antigen 9 (SPAG9) is associated with numerous cancers, including hepatocellular carcinoma (HCC). The exploration of molecules and mechanisms regulating SPAG9 expression may provide new options for HCC therapy. Methods: MiRNA target prediction programs were used to explore SPAG9-targeted miRNAs. SPAG9 and miR-141 expression were detected in HCC tissues and cell lines by Western blot and real-time PCR. Dual-luciferase reporter assay was utilized to validate SPAG9 as a direct target gene of miR-141. Cell proliferation, invasion, and migration assays were used to determine whether miR-141-mediated regulation of SPAG9 could affect HCC progression. Results: An inverse correlation was observed between SPAG9 and miR-141 expression in HCC tissues and cell lines. Dual-luciferase reporter assay further showed that SPAG9 was a direct target gene of miR-141. The ectopic expression of miR-141 could markedly suppress SPAG9 expression in HCC cells. MiR-141 overexpression also resulted in significantly reduced cell proliferation, invasion, and migration, and imitation of the SPAG9 knockdown effects on HCC cells. Furthermore, SPAG9 restoration in miR-141-expressing cells sufficiently attenuated the tumor-suppressive effects of miR-141. Finally, JNK activity was found to be reduced by miR-141 overexpression the same way as by SPAG9 silencing. The overexpression of SPAG9 lacking its 3'-UTR significantly restored JNK activity and its downstream genes in miR-141-transfected HCC cells. Conclusion: MiR-141 suppression may cause aberrant expression of SPAG9 and promote HCC tumorigenesis via JNK pathway.
    Preview · Article · Dec 2016 · Journal of Experimental & Clinical Cancer Research
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    • "Refs. First author, year Antigen Stage Case number Positive number Stage-specific sensitivity (%) Overall sensitivity (%) Specificity (%) [44] Chang, 2005 p53 I 20 6 30 28 a 100 II 54 12 22 III 58 20 35 IV 35 9 26 [16] Suppiah, 2008 p53 I 5 1 20 22 a 100 II 41 9 22 III 41 9 22 IV 4 1 25 [39] Kojima, 2011 p53 I 37 4 11 21 a 93 II 34 9 27 III 58 15 26 IV 13 2 15 [14] Kojima, 2009 p53 I 16 2 13 20 a 100 II 15 2 13 III 14 5 36 IV 0 0 - [21] Lechpammer, 2004 p53 I 28 0 0 18 a 100 II 87 9 10 III 105 9 9 IV 0 0 - [13] Tang, 2001 p53 I 17 1 6 13 a 99 II 439 53 12 III 321 39 12 IV 221 38 17 [60] Chen, 2011 Annexin A I 12 11 92 85 a 62 II 79 63 80 III 91 76 83 IV 38 37 97 [61] Fan, 2011 SEC61b I 10 8 80 79 a 75 II 25 19 76 III 35 29 83 IV 16 12 75 [33] Chen, 2011 RPH3AL I 5 3 60 73 a 84 II 29 18 61 III 34 27 80 IV 16 12 75 [62] Kocer, 2006 MUC5AC I 0 0 - 60 a 73 II 8 4 50 III 11 5 46 IV 11 8 73 [40] Chan, 2010 Panel of five antibody markers b I 7 5 7 1 5 9 a 93 II 34 17 50 III 38 22 58 IV 15 11 73 [20] Chen, 2010 Survivin I 13 8 65 57 a 64 II 86 50 58 III 92 52 57 IV 41 22 54 [51] Benmahrez, 1990 c-myc I 3 1 33 57 a 83 II 20 12 60 III 12 6 50 IV 8 5 63 [68] He, 2009 IMPDH2 I 2 1 50 32 a 100 II 6 1 17 III 14 4 29 IV 3 2 67 [39] Kojima, 2011 CEA I 37 4 11 9 a 94 II 34 3 9 III 58 5 9 IV 13 1 8 [32] Kanojia, 2011 SPAG9 I + II 12 12 100 70 100 III + IV 26 16 62 [35] Chen, 2012 AEG-1 I + II 20 6 30 49 a 100 III + IV 68 37 54 [67] Syrigos, 1999 Tropomyosin I + II 13 5 35 36 a 95 III + IV 32 12 38 "
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    ABSTRACT: Multiple studies have shown that cancer patients produce detectable autoantibodies against certain tumor-associated antigens, which might be promising blood biomarkers for early detection of CRC. We aimed to provide an overview of published studies on blood autoantibody markers for early detection of CRC and to summarize their diagnostic performance. A systematic literature search was performed in PubMed, ISI Web of Knowledge and EMBASE to find relevant studies published until 23 July 2013. Relevant information, such as study population characteristics, autoantibodies studied, analytical methods and diagnostic performance characteristics was independently extracted by two reviewers. Overall, 67 studies evaluating 109 autoantibody markers were included. Most individual markers showed low sensitivity (below 25%) for detecting CRC, along with high specificity close to 100%. Occasionally reported higher sensitivities for specific antibodies are yet to be replicated in independent studies. Generally, more promising results were seen for combinations of multiple autoantibody markers. But again, these promising results are yet to be replicated in other samples. In conclusion, autoantibody signatures may become a promising approach to noninvasive CRC screening. Optimized marker panels are yet to be developed, and promising results require validation in large screening populations.
    Full-text · Article · Jan 2014 · Cancer letters
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    • "The JNK has been proposed to play an important role in cell survival, proliferation and tumorigenesis [7]. SPAG9 expression was shown to be associated with epithelial ovarian cancer [8], renal cell carcinoma [9], breast cancer [10], cervix cancer [11], thyroid cancer [12] and colorectal carcinoma [13]. These observations and findings are suggestive of SPAG9 as potential target for the development of diagnostic and therapeutic interventions. "
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    ABSTRACT: Majority of bladder cancer deaths are caused due to transitional cell carcinoma (TCC) which is the most prevalent and chemoresistant malignancy of urinary bladder. Therefore, we analyzed the role of Sperm associated antigen 9 (SPAG9) in bladder TCC. We examined SPAG9 expression and humoral response in 125 bladder TCC patients. Four bladder cancer cell lines were assessed for SPAG9 expression. In addition, we investigated the effect of SPAG9 ablation on cellular proliferation, cell cycle, migration and invasion in UM-UC-3 bladder cancer cells by employing gene silencing approach. Our SPAG9 gene and protein expression analysis revealed SPAG9 expression in 81% of bladder TCC tissue specimens. High SPAG9 expression (>60% SPAG9 positive cells) was found to be significantly associated with superficial non-muscle invasive stage (P = 0.042) and low grade tumors (P = 0.002) suggesting SPAG9 putative role in early spread and tumorigenesis. Humoral response against SPAG9 was observed in 95% of patients found positive for SPAG9 expression. All four bladder cancer cell lines revealed SPAG9 expression. In addition, SPAG9 gene silencing in UM-UC-3 cells resulted in induction of G0-G1 arrest characterized by up-regulation of p16 and p21 and consequent down-regulation of cyclin E, cyclin D and cyclin B, CDK4 and CDK1. Further, SPAG9 gene silencing also resulted in reduction in cellular growth, and migration and invasion ability of cancer cells in vitro. Collectively, our data in clinical specimens indicated that SPAG9 is potential biomarker and therapeutic target for bladder TCC.
    Full-text · Article · Dec 2013 · PLoS ONE
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