Expression of folate receptors and heterogeneous nuclear ribonucleoprotein E1 in women with human papillomavirus mediated transformation of cervical tissue to cancer

Abstract

Aims: Folate receptors (FRs) mediate cellular uptake of folates in many cancer cells and in folate deficiency heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) mediates translational upregulation of FR in cultured cervical cancer cells. hnRNP-E1 can also interfere with human papillomavirus 16 (HPV-16) viral capsid protein synthesis (and thereby HPV proliferation) in vitro. This study aimed to evaluate prospectively the relevance of FR and hnRNP-E1 expression in the normal cervix, cervical dysplasia, and cancer. Methods: Cervical tissues from 12 women with normal histology and 69 consecutive women with varying grades of cervical dysplasia and cancer were prospectively evaluated for immunohistochemical expression of FR, hnRNP-E1, proliferating cell nuclear antigen (PCNA), and HPV. There were 22 women with low grade squamous intraepithelial lesions (LGSIL), 22 with high grade squamous intraepithelial lesions (HGSIL), and 25 with invasive cervical carcinoma. Results: Among normal subjects, 100% and 92% expressed hnRNP-E1 and FR, respectively. FR expression decreased from 91% in LGSIL to 68% and 64% in women with HGSIL and cancer, respectively. Similarly, hnRNP-E1 expression decreased from 86% in LGSIL to 68% and 40% in HGSIL and cancer, respectively. There was a highly significant positive correlation between the extent of FR and hnRNP-E1 expression, and an inverse correlation between HPV infection and hnRNP-E1 expression during progression of cervical dysplasia to cancer. Conclusion: These results are consistent with a hypothesis that reduced hnRNP-E1 expression may be permissive for HPV proliferation and progression to cervical cancer, and support the need for prospective longitudinal studies of hnRNP-E1 expression in HPV-16 infected women.

Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions

“…These results confirmed the critical role of the interaction of cis-element and hnRNP E1 in the translation of FRs (14). The recent identification of a significant correlation between the expression of FRs and hnRNP E1 in the cervixes of normal women and those with cervical dysplasia and cervical cancer further supports the idea of a physiologic relationship (16). However, the obvious "missing link" to a more comprehensive understanding of the translational regulation of FRs (via involvement of these components) in folate deficiency was the precise trigger(s) for the interaction of FR mRNA cis-element and the hnRNP E1 resulting in upregulation of FRs.…”

Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: Focus on hnRNP E1's multifunctional regulatory roles

“…This notion is reinforced by the observation that deficient expression of hnRNPs can cause significant telomere shortening and oncogenic transformation (LaBranche et al 1998). Reduced hnRNP E1 expression is also a prerequisite for human papillomavirus (HPV) proliferation and subsequent incidence of cervical carcinoma from cervical dysplasia (Pillai et al 2003). Recently, miR328 has been shown to function as a ''decoy'' for hnRNP E2.…”

RNA-binding protein PCBP2 modulates glioma growth by regulating FHL3

“…Transcriptional activation of the oncogenes c-SRC and c-Myc was increased by hnRNP K (5,6), suggesting that hnRNPK may cooperate with additional oncoproteins to overexpress genes that promote cancerous growth. PCBP1 has been reported to be downregulated in metastatic cervical cancer (7) and metastatic breast cancer cells (8). Knockdown of PCBP1 in the prostate cancer cell line LNCaP increased androgen receptor (AR) protein targeting to the 3′ untranslated region (UTR) of AR transcripts (9).…”