Expression of CHOP in Squamous Tumor of the Uterine Cervix

The endoplasmic reticulum (ER) is an essential intracellular organelle that serves important cellular functions. One of its major functions is to ensure proper folding of newly synthesized proteins destined for secretion, the cell surface, or intracellular organelles. Various physiological and pathological conditions lead to the accumulation of unfolded proteins in the ER, a condition referred to as "ER stress." In response to ER stress conditions, cells activate an intracellular signaling pathway, the unfolded protein response (UPR),1,2 which acts to reduce ER stress by activating three adaptive pathways: 1) transcriptional induction of ER chaperones to help protein folding; 2) translational attenuation of protein synthesis, which blocks new protein synthesis; and 3) enhanced degradation of misfolded or unfolded proteins via the ubiquitin-proteasome system.1,3 If the UPR is unable to rescue cells, the cells eventually enter apoptosis via increased C/EBP homologous protein (CHOP) expression or activation of ER-specific caspases. CHOP, also known as growth arrest and DNA damage-inducible protein 153 (GADD153), is a transcription factor induced by DNA damage and is activated in response to ER stress.4 CHOP plays an important role in ER stress-induced apoptosis and is widely used as an ER stress marker. Moreover, increased CHOP expression has been reported in some malignant tumors.5-7 On the other hand, p53 is one of the important apoptosis-related genes and is also involved in many other cellular processes such as cell cycle progression, DNA repair, differentiation, senescence, and chromatin remodeling.8 Impaired p53-dependent apoptosis due to high-risk human papillomavirus (HR-HPV) has been known as one of the key mechanisms of cervical carcinogenesis. Interestingly, CHOP is one of the many p53 target genes9,10 according to human cell studies. Cervical cancer is the second most common type of cancer in women worldwide.11 Human papillomaviruses (HPV) are the etiologic agents responsible for cervical cancer. Over 100 different types of HPV have been identified based on their DNA sequence.12 HPV types such as HPV 16 and HPV 18 are high oncogenic risk types. More than 99% of cervical cancers contain DNA from at least one HR-HPV type, and approximately 70% contain HPV 16 or 18.13 However, experimental and epidemiological evidences indicate that HR-HPV is not sufficient to induce tumor development. Other factors have to be involved in the progression of infected cells to full neoplastic transformation. Recent studies have shown that ER stress may facilitate viral replication or pathogenesis.14 The ER is an essential organelle for viral replication and maturation. A large number of viral proteins are produced in infected cells, where unfolded or misfolded proteins activate the ER stress response. There are some reports regarding the role of ER stress in HPV infection. Accordingly, ER stress responses were repressed in HPV 16 infected genital keratinocytes.15 ER protein 57 (ERp57), one of the ER stress markers, was induced in HPV 16 positive squamous cell carcinoma (SqCC) of uterine cervix.16 Based on these reports, we hypothesized that CHOP is involved in the carcinogenesis of uterine cervical cancer in association with HR-HPV and/or p53. To test this, we conducted immunohistochemical studies to assess CHOP and p53 expression in cervical intraepithelial neoplasms (CIN) and invasive SqCC of the uterine cervix. We also investigated the association between CHOP expression and HR-HPV infection.