Three Prime Repair Exonuclease 1 (TREX1) expression correlates with cervical cancer cells growth in vitro and disease progression in vivo

Abstract

Alterations in specific DNA damage repair mechanisms in the presence of human papillomavirus (HPV) infection have been described in different experimental models. However, the global effect of HPV on the expression of genes involved in these pathways has not been analyzed in detail. In the present study, we compared the expression profile of 135 genes involved in DNA damage repair among primary human keratinocytes (PHK), HPV-positive (SiHa and HeLa) and HPV-negative (C33A) cervical cancer derived cell lines. We identified 9 genes which expression pattern distinguishes HPV-positive tumor cell lines from C33A. Moreover, we observed that Three Prime Repair Exonuclease 1 (TREX1) expression is upregulated exclusively in HPV-transformed cell lines and PHK expressing HPV16 E6 and E7 oncogenes. We demonstrated that TREX1 silencing greatly affects tumor cells clonogenic and anchorage independent growth potential. We showed that this effect is associated with p53 upregulation, accumulation of subG1 cells, and requires the expression of E7 from high-risk HPV types. Finally, we observed an increase in TREX1 levels in precancerous lesions, squamous carcinomas and adenocarcinomas clinical samples. Altogether, our results indicate that TREX1 upregulation is important for cervical tumor cells growth and may contribute with tumor establishment and progression.

Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-κB Activation in Oral Cancer Cells

“…It has been widely reported that HPV oncoproteins promote DNA damage and OS involved in cancer initiation and progression [ 31 , 32 , 33 ]. However, the role of E7 oncoprotein in oral cancer progression has not been sufficiently addressed, although it is critical for immortalization and cell transformation [ 34 ].…”

Biological and clinical aspects of HPV-related cancers

“…A recent study proposed E7 as the oncoprotein which hampers the DNA damage response to DSBs by interacting with the E3 ligase RNF168 involved in DNA DSB repair 62 . It has also been observed that expression of an exonuclease with a proofreading function, Three prime repair exonuclease 1 (TREX1), is upregulated exclusively in HPV-transformed primary keratinocytes expressing HPV 16 E6 and E7 77 . Downregulation of TREX1 resulted in inhibition of cell growth, which was associated with p53 upregulation.…”

Rapidly Progressing Early Puberty in a Boy with Bilateral Basal Ganglia Germinoma and TREX1 Variant

“…Recently, several studies have reported the association between the TREX1 and tumorigenesis. Prati et al (6) indicated that TREX1 upregulation was an important factor for the growth of cervical tumor cells and may contribute to tumor progression. Also, malfunction of DNA mismatch repair genes, including TREX1, has been reported to be associated with a risk of gastric cancer by causing microsatellite instability (5).…”

“…Vanpouille-Box et al (13) identified TREX1 as a key determinant for the limited immunogenicity of cancer cells responding to single high-dose radiation. The role of TREX1 in carcinogenesis is still unclear, but recent studies have shown that the alteration of TREX1, which is essential for DNA damage repair and elimination of cytoplasmic DNA, consequently preventing the activation of innate immune mechanisms, may lead to cancer development (6).…”

“…These are known to be associated with Aicardi-Gouitères syndrome, systemic lupus erythematosus, and familial chilblain lupus (3,4). Recently, several studies have reported the association between TREX1 and carcinogenesis in gastric cancer and cervical cancer (5,6).…”