CYB5D2 displays tumor suppression activities towards cervical cancer

• Published in: Biochimica et biophysica acta 2016-04, Vol.1862 (4), p.556-565
• Main Authors: Xie, Yanyun, Shen, Yen Ting, Kapoor, Anil, Ojo, Diane, Wei, Fengxiang, De Melo, Jason, Lin, Xiaozeng, Wong, Nicholas, Yan, Judy, Tao, Lijian, Major, Pierre, Tang, Damu
• Format: Article
• Language: English
• Subjects: Animals; Cervical cancer; CYB5D2; Cytochromes b5 - biosynthesis; Cytochromes b5 - genetics; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HEK293 Cells; HeLa Cells; Humans; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Neoplasm Invasiveness; Tumor suppressor; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics; Uterine Cervical Neoplasms - enzymology; Uterine Cervical Neoplasms - genetics; Xenograft tumors
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2015.12.013

Cervical cancer is caused by infections with human papillomaviruses (HPV) and genetic alternations in the cervical epithelium. While the former is well studied, the latter remains unclear. We report here that CYB5D2/Neuferricin possesses tumor suppressing activity towards cervical tumorigenesis. Ectopic expression of CYB5D2 did not affect HeLa cell proliferation and the cell's ability to form xenograft tumors, but significantly inhibited HeLa cell invasion in vitro and the cell-produced lung metastasis in NOD/SCID mice. Knockdown of CYB5D2 enhanced HeLa cell invasion. Two mutations in CYB5D2, the substitutions of arginine (R) 7 with either proline (P) or glycine (G), were reported in colon cancer. Both CYB5D2(R7P) and CYB5D2(R7G) were incapable of inhibiting HeLa cell invasion. CYB5D2 binds heme, in which aspartate (D) 86 is required. While CYB5D2(D86G) is heme-binding defective, it inhibited HeLa cell invasion. On the other hand, CYB5D2(R7P) and CYB5D2(R7G) bound heme but did not inhibit HeLa cell invasion. Collectively, CYB5D2 inhibits HeLa cell invasion independently of its heme binding. Furthermore, immunohistochemistry examination of CYB5D2 expression in 20 normal cervical tissues and 40 cervical squamous cell carcinomas (SCC) revealed a CYB5D2 reduction in 87.5% (35/40) of SCC. Analysis of CYB5D2 gene expression and genomic alteration data available from Oncomeine™ detected significant reductions of CYB5D2 mRNA in 40 SCCs and CYB5D2 gene copy number in 107 SCCs. Collectively, we provide evidence that CYB5D2 is a candidate tumor suppressor of cervical tumorigenesis. •CYB5D2 is a novel tumor suppressor by suppressing cervical cancer tumorigenesis.•CYB5D2 inhibits HeLa cell invasion in vitro and lung metastasis in vivo.•CYB5D2 is reduced in 85% of primary squamous cell carcinomas of the cervix.•CYB5D2 suppresses cervical cancer independently of its association with heme.