Expression of prion protein is closely associated with pathological and clinical progression and abnormalities of p53 in head and neck squamous cell carcinomas
- Authors:
- Published online on: November 16, 2015 https://doi.org/10.3892/or.2015.4425
- Pages: 817-824
Abstract
Introduction
Head and neck squamous cell carcinoma (HNSCC) is a group of common malignant cancers located in the oral cavity, hypopharynx, oropharynx and larynx (1). Annually, HNSCCs account for more than 550,000 cases of cancer worldwide (2). Research suggests that tobacco use and alcohol consumption are two major risk factors for HNSCC. Human papillomaviruse (HPV) infection, particularly high-risk HPVs, are closely associated with HNSCCs, particularly carcinomas of the lip and oral cavity (3,4). The tumor-suppressor p53, which plays essential roles in many different types of human malignant tumors, was also found to be associated with the occurrence of HNSCC (5). Various types of mutations in the p53-encoding gene (TP53) have been identified in HNSCC tissues (6). In addition, various single-nucleotide polymorphisms (SNPs) in TP53, such as the polymorphism in codon 72 (SNP72), significantly influence the age at onset of various types of HNSCCs (7).
Prion protein (PrP) is a copper binding glycoprotein, which is highly conserved throughout evolution (8). PrP exists in many types of tissues, but is mostly concentrated in the central nervous system (CNS). PrP is directly involved in prion diseases or transmissible spongiform encephalopathies (TSEs) that are a group of fatal neurodegenerative diseases, such as human Creutzfeldt-Jakob disease (CJD), scrapie and bovine spongiform encephalopathy. In these cases, normal cellular PrP (PrPC) is converted into a proteinase-resistant and pathological isoform (PrPSc) (9). As a cellular membrane protein, normal PrP is expressed in the neurons and glia of the brain and spinal cord, as well as in several peripheral tissues and in leukocytes (10). The efficient transcription of PrP is detectable in the brains of mice and chickens beginning early in embryogenesis, and its level increases as development proceeds (11). Although its wide expression in many cell types indicate a more cosmopolitan biological function, the exact cellular function remains undefined. Evidence suggests that PrPC is important for synaptic activity, cell adhesion and recognition, ligand uptake, transmembrane signaling and neuroprotection (12). The biological function of PrP in peripheral tissues has been rarely addressed.
In the past decade, the association of PrP with human malignant tumors has attracted great attention. PrP has been found to be overexpressed in a variety of cancers including gastric, pancreatic and breast cancers, osteosarcoma and melanoma (13–15). Various studies have even proposed that overexpression of PrP is closely associated with the poor prognosis of pancreatic and breast cancers, highlighting that it may affect the growth and invasiveness of cancers (16). PrP expression is also believed to play an important role in the acquisition of multidrug-resistant (MDR) gastric cancer (17). However, the expression of PrP and its role in HNSCCs remain undescribed.
In the present study, PrP expression in tumor tissues from 92 pathologically diagnosed HNSCC cases were screened with PrP-specific immunohistochemical assays. We found that 55.43% (51/92) of the tested carcinomas were PrP-positive. The positive rate and the staining intensity of PrP were closely related with the pathological degree of the tumors. Additionally, PrP-positive rates also showed correlations with the anatomic site and the clinical grade of the carcinomas. Further evaluation of the associations of PrP expression with p53 abnormalities and HPV infection in malignant tissues revealed that PrP-positive staining was more frequently detected in the tissues with p53-positive accumulation and the wild-type TP53 gene.
Materials and methods
Specimens
The paraffin-embedded specimens of HNSCCs used in our previous studies (7,18) were employed in the present study, except one laryngocarcinoma case without further available tissue. Totally, 92 HNSCCs were recruited, including 63 laryngocarcinoma, 5 oropharyngeal, 15 hypopharynx and 9 lip carcinomas. All patients were hospitalized at the Department of Head and Neck Surgery, Peking University Cancer Hospital and Institute, from 2006 to 2011. The demographic, clinical and pathological information of these patients was previously described (18). Six surgically removed tissues from the patients with laryngocarcinoma were stored at −80°C.
Immunohistochemistry (IHC)
Paraffin sections (5-µm in thickness) were deparaffinized in xylene for 5 min twice and gradually routinely rehydrated. The sections were quenched for endogenous peroxidases in 3% H2O2 in methanol for 15 min, and pretreated with enzyme digestion antigen retrieval for 1 min. After blocking in 1% normal goat serum, the sections were incubated overnight at 4°C with 1:500-diluted PrP-specific mAbs, including 3F4 (MAB1562; Millipore), 6D11 (sc-58581), 7D9 (sc-58582) (both from Santa Cruz Biotechnology) and 8H4 (ab-61409; Abcam). The sections were then incubated for 60 min with 1:1,000-diluted HRP-conjugated goat anti-mouse secondary antibody (Vector Labs, USA), and visualized by incubation with 3,3-diaminobenzidine tetrahydrochloride (DAB). The slices were dehydrated and mounted in Permount. Photomicrographs were captured with a DP70 digital camera mounted on a BX5 microscope (Olympus Optical, Japan).
Determination of the degree of PrP-positive staining
The strategy for determination of the degree of PrP-positive staining in the tested tissues was based on a protocol described elsewhere (19). Briefly, five fields under microscopy were randomly selected for each slice. The score was given based on the ratio of positively stained cells and gradation of the stained color. A total of <10% positive cells was recorded as 0, 10–25% as 1, >25–50% as 2, >50–75% as 3, and >75% as 4. No positive staining was scored as 0, light brown signals in cells was scored as 1, brown signals in cells was scored as 2, deep brown signals was scored as 3. The score of the percentage of positive cells and the score of the gradation of the stained color was multiplied and the final result was given based on the product: 0–1 as negative (−), 2–4 as weakly positive (+), 5–8 as positive (++), 9–12 as strongly positive (+++).
Preparation of tissue homogenates
The tissue samples of HNSCC and the brain samples of normal and scrapie-infected mice were homogenized in 10% lysis buffer (w/v, 100 mM NaCl, 10 mM EDTA, 0.5% Nonidet P-40, 0.5% sodium deoxycholate, 10 mM Tris, pH 7.5) according to a protocol described elsewhere (20). Then, tissue debris was removed with low speed centrifugation at 2,000 × g for 10 min and the supernatants were collected for further study.
Ethics statement
Written consent for further investigation and publication was obtained from the patients or the patients' relatives, respectively. Usage of the stored human samples in the present study was approved by the Ethics Committees of Peking University Cancer Hospital and the Institute and National Institute for Viral Disease Prevention and Control, China CDC.
Statistical analysis
Statistical analysis was performed using Chi-square and Fisher's exact tests for correlations between groups for HPV infection, SNP72 type, p53 mutation and IHC. Mann-Whitney method was used for the relationship between SNP72 and age. A probability value of <0.05 was considered to indicate a statistically significant result. All statistical analyses were performed by SPSS 20 (IBM, USA).
Results
PrP expression is detectable in more than half of the carcinoma tissues
PrP protein is widely expressed in CNS. To ascertain the expression of PrP in HNSCC tissues, several commercial PrP monoclonal antibodies were selected and screened for the potential usage in the IHC assays: mAbs 3F4, 6D11, 7D9 and 8H4. Using the sections from the same paraffin-embedded tissues of 3 different patients, the immunoreactivities of the mAbs were comparably evaluated under the same experimental conditions. mAb 3F4 produced the most significant reactivity in the IHC assays, with clear brown positive staining in the cytoplasm and membrane of the carcinoma cells. Therefore, PrP-specific mAb 3F4 was used in the IHC assays in the subsequent tests.
Totally, 92 slices were stained with mAb 3F4 immunofluorescently, and 51 cases (55.43%) were PrP-positive. Based on the judgment protocol described above, 41 (44.57%) cases were weakly positive for PrP (+), 9 (9.78%) were PrP positive (++) and only one case was strongly positive for PrP (+++). As shown in Fig. 1, the PrP-specific staining was concentrated in the carcinoma cells, mostly distributed in the cytoplasm. In some areas, the strongly positive staining formed large positive masses. PrP-positive staining was rarely observed in the regions of morphologically normal tissues.
Among the 92 tested HNSCC specimens, 63 were located in the larynx, 5 in the oropharynx, 15 in the hypopharynx and 9 in the lip. PrP expression was positive in 44.44% (4/9) of the lip carcinomas, 60% (3/5) of the oropharyngeal carcinomas, 46.67% (7/15) of the hypopharynx carcinomas and 58.73% (37/63) of the laryngeal carcinomas (Table I). Statistical analysis showed significantly higher PrP expression in the cancers of the oropharynx and larynx.
Correlation between PrP expression and the clinical degrees of the HNSCCs
To test the potential correlation between PrP-positive staining and the clinical grade at the time of surgical operation, 92 of the HNSCCs were grouped according to their clinical degrees. The PrP-positive rates of clinical degree I, II, III and IV cases were 44.44 (12/27), 62.86 (22/35), 56 (14/25) and 60% (3/5), respectively (Table II). Statistical assays revealed significantly low PrP-positive rates in the group of clinical degree I than that in II (P=0.0001), III (P=0.0199) and IV (P=0.0015). There was no statistical difference in the PrP-positive rate among the tumors of clinical degree II, III and IV. The distributions of the PrP-positive carcinomas based on the intensities were quite comparable. Tumor tissues in later clinical degree had higher PrP-positive rates.
Correlation between PrP expression and the pathological grade of the HNSCCs
To ascertain the possible relationship between PrP expression and pathological differentiation, the tested HNSCCs were divided into groups of low, moderately and highly differentiated carcinomas. The PrP-positive rates were 30.77% (8/26) in the highly differentiated, 60.78% (31/51) in the moderately differentiated and 80% (12/15) in the lowly differentiated HNSCCs, respectively (Table III). Statistical analysis obviously showed significance among the three groups and between each group (P<0.0001). Further analysis identified that 8 out of 9 PrP-positively stained (++) cases were distributed in the groups of moderately and lowly differentiated carcinomas, and one strongly PrP-positive (+++) case was poorly differentiated carcinoma. This strongly indicates a close association of PrP expression with poorly differentiated HNSCCs.
Correlation between the PrP expression and abnormalities of p53 in the HNSCCs
Our previous study proposed that among all 92 HNSCC cases, 37 cases (40.22%) were p53-positive and 55 cases (59.78%) were p53-negative. Sequencing analysis of the TP53 gene revealed that 34 (36.96%) cases contained various mutations (7). Analysis of the possible relationship between PrP and p53 staining in IHC identified that the rate of PrP-positive staining was 64.86% (24/37) in the p53-positive patients, while the rate was 49.09% (27/55) in the p53-negative patients, showing statistical difference (P=0.0041) (Fig. 2A). All 6 HNSCC cases showing p53 strong positive p53 staining was also PrP-positive. In contrary, positive staining for PrP was detected in 44.11% (15/34) of the patients containing mutations in TP53 and 62.07% (36/58) of those without a mutation in TP53, showing high significance (P=0.0002) (Fig. 2B). This indicates that the patients with p53-positive cancer cells and the patients with the wild-type TP53 gene had a higher possibility to be PrP-positive.
To ascertain the possible linkage of PrP-positive staining with the intensities of the p53-positive staining in the IHC assays, 37 p53-positive cases in IHC were grouped as weakly positive (p53 IHC+) (18 cases) and strongly positive (p53 IHC++) (19 cases). The positive rates of PrP expression in the groups of p53 IHC+ and p53 IHC++ were 66.67% (12/18) and 63.15% (12/19), respectively, without statistical difference in the PrP-positive rate (P>0.05) (Fig. 2C). Furthermore, the cases with PrP-positive expression in the 37 cases with p53-positivity in IHC were analyzed according to whether they had mutations in their TP53 gene. Out of 17 patients with mutations in TP53, 58.82% (10/17) were PrP-positive, while out of 20 patients with wild-type TP53, 65.00% (13/20) were PrP-positive (Fig. 2D). Although the PrP-positive rate in the patients with p53-positive staining and mutated TP53 was slightly lower than in the patients with p53-positive staining and wild-type TP53, statistical analysis did not achieve significance (P>0.05). This highlights that either the intensity of p53-positive staining or the status of TP53 did not notably influence the PrP expression in the group of p53-positive HNSCCs.
Single-nucleotide polymorphisms (SNPs) in codon 72 (SNP72) of TP53 include arginine (Arg)/Arg, Pro/Pro and Pro/Arg. Among the 91 HNSCCs with data for p53 SNP72, 29 cases were Arg/Arg homozygote whose phenotype is nominated as Arg, 62 were Pro/Pro homozygote or Pro/Arg heterozygote whose phenotype is termed as Pro (7). The distributions of PrP-positive rates in these two groups were obviously different; the PrP-positive rate in the group of Pro/Pro homozygotes or Pro/Arg heterozygotes (61.29%, 38/62) was significantly higher than those of the Arg/Arg homozygote (44.83%, 13/29), indicating a close correlation between PrP expression and p53 SNP72 (Fig. 2E).
Correlation between PrP expression and HPV infection in HNSCCs
Among the 92 HNSCCs, HPV-related sequences and/or proteins were detectable in 40 cases. The positive rates of PrP immunostaining were 57.50% (23/40) and 55.76% (29/52) in the HPV-positive and -negative cases, respectively. No statistical difference in PrP expression was found between the HPV+ and HPV− groups (P>0.05) (Fig. 3A). Among the 40 HPV-positive HNSCCs, 12 were HPV sequence positive only, and 24 were HPV early (E6/E7) protein positive only, and 4 were HPV sequence and protein positive both (18). Obvious expression of PrP was detected in half of the patients in the HPV sequence positive (HPV Seq+) and HPV sequence and protein positive (HPV IHC+/Seq+) groups, but in 62.5% of the patients showing HPV protein positivity (HPV IHC+), showing statistical difference (P<0.05) (Fig. 3B). Additionally, 4 out of 9 HPV16 sequence-positive cases and 4 out of 7 HPV18 sequence-positive cases were PrP-positive, without statistical significance (Fig. 3C). These data indicate that HPV infection does not influence the expression of PrP in malignant cells.
Discussion
In the present study, we screened the PrP expression in malignant tissues of HNSCCs with IHC. PrP-positive staining was observable in 55.43% of the tested HNSCCs. The positive rate and the intensity of PrP in the tumor tissues were closely associated with the pathological grade of the carcinomas. Meanwhile, the PrP-positive rate was correlated with the anatomic site and clinical degree of the HNSCCs. Additionally, the HNSCCs with p53-positivity in IHC and the Pro/Pro and Pro/Arg genotypes in SNP27 of p53 showed a higher probability for positive expression of PrP in their cells. PrP expression in the HNSCCs were not related with HPV infections.
Apart from its indispensible and unique role in human and animal prion diseases, a disparate significance of PrP in human malignant tumors has attracted great attention. Numerous lines of evidence support the potential involvement of PrP in different types of human cancers, in which PrP is overexpressed, such as colorectal (21), gastric (22,23) breast (24,25), pancreatic (26,27) and prostrate (28). In addition, PrP expression is observable in many tumor cell lines derived from the above malignant tumors or from other cancers, such as melanoma and hepatocarcinoma (16,27). However, the PrP status in cancer derived from squamous cells appears to be rarely described, except a report of oral squamous cell carcinomas in a Chinese journal (29). Our data in the present study strongly indicate a distinct involvement of PrP protein in the cancer biology of squamous cell carcinoma, at least HNSCCs.
Despite the diversities of the PrP-positive rates in different types of cancers from different studies, a close correlation between PrP expression and pathological and clinical grades of cancers has been well documented in almost all studies (16,27). The frequency of PrP expression was found to be ~40% in patients with pancreatic ductal cell adenocarcinoma, but only 13% in pancreatic intraepithelial neoplasia (PIN)-3 cases and none in PIN-2 and -1 cases (27). Higher PrP-positive rates and stronger PrP staining are also noted in breast and gastric cancers (24,30). More importantly, PrP expression appears to be associated with poor prognosis in pancreatic and breast cancers (24), which highlights a contributory role of PrP in tumor progression. In line with the above observations, our data confirmed that the positive rates and staining intensities of PrP correlate well with the progression of HNSCCs, particularly the pathological grade of the tumors, which emphasizes again a common phenomenon in different human malignant tumors. Further prospective analysis of the relationship between the survival times and PrP expression in HNSCCs will help to define the prognostic value of PrP IHC assays.
Disruption of the p53 network favours cell survival and tumor progression. Abnormalities of p53, either mutations in TP53 or overexpression, are frequently observed in a number of human cancers, including HNSCCs, which is likely to be associated with increased susceptibility to cancer development. Our data in the present study illustrated a positive correlation of PrP expression with p53- positive IHC but a negative correlation with mutated TP53 in the HNSCCs. The exact biological meanings of such a pattern remain unclear. Recently, the abnormal accumulation of either WT or mutant p53 in the cytoplasm and nucleus were described in human cancers, such as neuroblastoma, retinoblastoma, breast and colon cancers (31–34). Notably, the aggregation of p53 could be amyloid-like, which highlights a possibility that p53 amyloid formation may participate in the malignant process (35).
SNP72 in TP53 is able to influence the function of p53, in which TP53 encoding Arg is more effective than that encoding Pro at inducing apoptosis and preventing cells from neoplastic development (7). The significance of the SNP72 polymorphism in association with the susceptibility of several types of cancers and the survival of cancer patients have been proposed (36). Our previous study found that HNSCC patients with a Pro polymorphism showed average younger onset-age and had higher percentages of strong p53-positivity in IHC (7). Coincidental with the clinical and pathological features of SNP72, we revealed that the patients with a Pro polymorphism in SNP72 had a significantly higher PrP-positive rate in the present study. This may indicate a possible cooperative effect of PrP and p53 in cancer biology.
HPV infections are frequently detected in HNSCCs (3,37). Among the tested 92 HNSCCs in the present study, 40 cases showed HPV positivity, either HPV sequences or proteins. We did not observe a notable difference in PrP expression between HPV-positive and HPV-negative groups, implying that HPV infection has little effect on PrP expression in HNSCCs. HPV infection in the 92 HNSCCs showed an anatomic increasing trend from inside to outside; more HPV-positive cases were noted in the lip and oropharynx than in the hypopharynx and larynx (18). However, PrP expression in the HNSCCs did not reveal anatomic-dependent alteration. As the limited numbers of other HNSCCs besides laryngeal cancers, a final conclusion of the relationship between HPV infection and PrP expression in HNSCCs requires large score assays.
Cellular PrP appears to be involved in many essential biological processes, such as cell adhesion, neurite outgrowth, synaptic transmission, oxidative stress, anti-apoptosis and neuroprotection, which are closely associated with cellular survival, proliferation and differentiation (38,39). Therefore, it is reasonable to speculate whether aberrant PrP function may contribute to tumorigenesis. However, numerous studies including ours demonstrated that the PrP proteins in cancer cells are an aglycosyl form of PrP or so-called 'pro-prion', which accumulate mainly in the cytoplasm but do not anchor on the cell membrane (40). In this situation, it is hard to simply attribute the role of PrP in tumorigenesis to its aberrantly enhanced biological effects. In fact, accumulation of aglycosyl PrP (not PrPSc) in the cytoplasm usually reduces the viability of many different types of cultured cell lines. Recently, many potential mechanisms have been proposed to explain the possible role of PrP in cancer cells, such as activation of the PI3K/Akt signaling pathway to upregulate cyclin D in gastric cancer cells (41), chemotherapy drug-induced PrP interaction with P-glycoprotein (P-gp; ATP-dependent drug-efflux pumps ABCB1) in drug-resistant MCF7 breast cancer cells, enhanced doxorubicin resistance via the ERK1/2 signaling pathway in MDA-MB-435 breast cancer cells (42), the fatal attraction between pro-PrP to filamin A in melanoma and pancreatic cancer cells (26). Nevertheless, a more comprehensive knowledge of PrPs may facilitate the understanding of the pathogenesis and the development of more effective tools for diagnosis, prognosis, therapy and prevention not only for TSEs, but also for a number of cancers.
Acknowledgments
The present study was supported by the Chinese National Natural Science Foundation Grants (81301429 and 81572048), the China Mega-Project for Infectious Disease (2011ZX10004-101 and 2012ZX10004215), and the SKLID Development Grant (2012SKLID102 and 2015SJLID503).
References
|
Inglehart RC, Scanlon CS and D'Silva NJ: Reviewing and reconsidering invasion assays in head and neck cancer. Oral Oncol. 50:1137–1143. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Machiels JP, Lambrecht M, Hanin FX, Duprez T, Gregoire V, Schmitz S and Hamoir M: Advances in the management of squamous cell carcinoma of the head and neck. F1000Prime Rep. 6:442014. View Article : Google Scholar : PubMed/NCBI | |
|
Kaba G, Dzudzor B, Gyasi RK, Asmah RH, Brown CA, Kudzi W and Wiredu EK: Human papillomavirus genotypes in a subset of head and neck squamous cell carcinoma. West Afr J Med. 33:121–124. 2014.PubMed/NCBI | |
|
Woods R Sr, O'Regan EM, Kennedy S, Martin C, O'Leary JJ and Timon C: Role of human papillomavirus in oropharyngeal squamous cell carcinoma: A review. World J Clin Cases. 2:172–193. 2014.PubMed/NCBI | |
|
Dang M, Lysack JT, Wu T, Matthews TW, Chandarana SP, Brockton NT, Bose P, Bansal G, Cheng H, Mitchell JR, et al: MRI texture analysis predicts p53 status in head and neck squamous cell carcinoma. AJNR Am J Neuroradiol. 36:166–170. 2015. View Article : Google Scholar | |
|
Maruyama H, Yasui T, Ishikawa-Fujiwara T, Morii E, Yamamoto Y, Yoshii T, Takenaka Y, Nakahara S, Todo T, Hongyo T, et al: Human papillomavirus and p53 mutations in head and neck squamous cell carcinoma among Japanese population. Cancer Sci. 105:409–417. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Shi Q, Xiao K, Wei W, Zhang BY, Chen C, Xu Y, Chen LN, Song YT, Ma X, Zhang NS, et al: Associations of TP53 mutations, codon 72 polymorphism and human papillomavirus in head and neck squamous cell carcinoma patients. Oncol Rep. 30:2811–2819. 2013.PubMed/NCBI | |
|
Colby DW and Prusiner SB: Prions. Cold Spring Harb Perspect Biol. 3:a0068332011. View Article : Google Scholar : PubMed/NCBI | |
|
Liberski PP: Historical overview of prion diseases: A view from afar. Folia Neuropathol. 50:1–12. 2012.PubMed/NCBI | |
|
Gasperini L and Legname G: Prion protein and aging. Front Cell Dev Biol. 2:442014. View Article : Google Scholar : PubMed/NCBI | |
|
Llorens F, Ferrer I and del Río JA: Gene expression resulting from PrPC ablation and PrPC overexpression in murine and cellular models. Mol Neurobiol. 49:413–423. 2014. View Article : Google Scholar | |
|
Yusa S, Oliveira-Martins JB, Sugita-Konishi Y and Kikuchi Y: Cellular prion protein: From physiology to pathology. Viruses. 4:3109–3131. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
He M, Wang L, Pu J, Yang Q, Li G and Hao J: Proliferin-related protein overexpression in SGC-7901 gastric cancer cells inhibits in vitro cell growth and tumorigenesis in nude mice. Oncol Rep. 29:2243–2248. 2013.PubMed/NCBI | |
|
Sy MS, Altekruse SF, Li C, Lynch CF, Goodman MT, Hernandez BY, Zhou L, Saber MS, Hewitt SM and Xin W: Association of prion protein expression with pancreatic adenocarcinoma survival in the SEER residual tissue repository. Cancer Biomark. 10:251–258. 2011–2012. | |
|
Farah J, Sayah R, Martinetti F, Donadille L, Lacoste V, Hérault J, Delacroix S, Nauraye C, Vabre I, Lee C, et al: Secondary neutron doses in proton therapy treatments of ocular melanoma and craniopharyngioma. Radiat Prot Dosimetry. 161:363–367. 2014. View Article : Google Scholar | |
|
Antony H, Wiegmans AP, Wei MQ, Chernoff YO, Khanna KK and Munn AL: Potential roles for prions and protein-only inheritance in cancer. Cancer Metastasis Rev. 31:1–19. 2012. View Article : Google Scholar : | |
|
Hinton C, Antony H, Hashimi SM, Munn A and Wei MQ: Significance of prion and prion-like proteins in cancer development, progression and multi-drug resistance. Curr Cancer Drug Targets. 13:895–904. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Wei W, Shi Q, Guo F, Zhang BY, Chen C, Zhang NS and Dong XP: The distribution of human papillomavirus in tissues from patients with head and neck squamous cell carcinoma. Oncol Rep. 28:1750–1756. 2012.PubMed/NCBI | |
|
Gao JM, Gao C, Han J, Zhou XB, Xiao XL, Zhang J, Chen L, Zhang BY, Hong T and Dong XP: Dynamic analyses of PrP and PrPSc in brain tissues of golden hamsters infected with scrapie strain 263K revealed various PrP forms. Biomed environ Sci. 17:8–20. 2004.PubMed/NCBI | |
|
Zhang J, Chen L, Zhang BY, Han J, Xiao XL, Tian HY, Li BL, Gao C, Gao JM, Zhou XB, et al: Comparison study on clinical and neuropathological characteristics of hamsters inoculated with scrapie strain 263K in different challenging pathways. Biomed Environ Sci. 17:65–78. 2004.PubMed/NCBI | |
|
Antonacopoulou AG, Palli M, Marousi S, Dimitrakopoulos FI, Kyriakopoulou U, Tsamandas AC, Scopa CD, Papavassiliou AG and Kalofonos HP: Prion protein expression and the M129V polymorphism of the PRNP gene in patients with colorectal cancer. Mol Carcinog. 49:693–699. 2010.PubMed/NCBI | |
|
Duhayon S, Hoet P, Van Maele-Fabry G and Lison D: Carcinogenic potential of formaldehyde in occupational settings: A critical assessment and possible impact on occupational exposure levels. Int Arch Occup Environ Health. 81:695–710. 2008. View Article : Google Scholar | |
|
Pan Y, Zhao L, Liang J, Liu J, Shi Y, Liu N, Zhang G, Jin H, Gao J, Xie H, et al: Cellular prion protein promotes invasion and metastasis of gastric cancer. FASEB J. 20:1886–1888. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Meslin F, Conforti R, Mazouni C, Morel N, Tomasic G, Drusch F, Yacoub M, Sabourin JC, Grassi J, Delaloge S, et al: Efficacy of adjuvant chemotherapy according to Prion protein expression in patients with estrogen receptor-negative breast cancer. Ann Oncol. 18:1793–1798. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Liang J, Pan YL, Ning XX, Sun LJ, Lan M, Hong L, Du JP, Liu N, Liu CJ, Qiao TD, et al: Overexpression of PrPC and its antiapoptosis function in gastric cancer. Tumour Biol. 27:84–91. 2006. View Article : Google Scholar | |
|
Li C, Yu S, Nakamura F, Yin S, Xu J, Petrolla AA, Singh N, Tartakoff A, Abbott DW, Xin W, et al: Binding of pro-prion to filamin A disrupts cytoskeleton and correlates with poor prognosis in pancreatic cancer. J Clin Invest. 119:2725–2736. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Sy MS, Li C, Yu S and Xin W: The fatal attraction between pro-prion and filamin A: Prion as a marker in human cancers. Biomarkers Med. 4:453–464. 2010. View Article : Google Scholar | |
|
Sauer H, Dagdanova A, Hescheler J and Wartenberg M: Redox-regulation of intrinsic prion expression in multicellular prostate tumor spheroids. Free Radic Biol Med. 27:1276–1283. 1999. View Article : Google Scholar | |
|
Zhang J, Zeng Y, Zheng J and Xu J: Expression of Prion protein and its clinical significance in oral squamous cells carcinoma and oral leukoplakia. Zhonghua Kou Qiang Yi Xue Za Zhi. 48:752–754. 2013.In Chinese. | |
|
Wang JH, Du JP, Zhang YH, Zhao XJ, Fan RY, Wang ZH, Wu ZT and Han Y: Dynamic changes and surveillance function of prion protein expression in gastric cancer drug resistance. World J Gastroenterol. 17:3986–3993. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Courtney R and Ranganathan S: Simultaneous adrenocortical carcinoma and neuroblastoma in an infant with a novel germline p53 mutation. J Pediatr Hematol Oncol. 37:215–218. 2015. View Article : Google Scholar | |
|
Seema R, Parul S, Nita K and Kamlesh: High-risk histomorphological features in retinoblastoma and their association with p53 expression: An Indian experience. Indian J Ophthalmol. 62:1069–1071. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Li ZD, Wang K, Yang XW, Zhuang ZG, Wang JJ and Tong XW: Expression of aryl hydrocarbon receptor in relation to p53 status and clinicopathological parameters in breast cancer. Int J Clin Exp Pathol. 7:7931–7937. 2014. | |
|
Read ML, Seed RI, Modasia B, Kwan PP, Sharma N, Smith VE, Watkins RJ, Bansal S, Gagliano T, Stratford AL, et al: The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer. Mol Carcinog. Nov 18–2014.Epub ahead of print. PubMed/NCBI | |
|
Silva JL, De Moura Gallo CV, Costa DC and Rangel LP: Prion-like aggregation of mutant p53 in cancer. Trends Biochem Sci. 39:260–267. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Al-Qasem A, Toulimat M, Tulbah A, Elkum N, Al-Tweigeri T and Aboussekhra A: The p53 codon 72 polymorphism is associated with risk and early onset of breast cancer among Saudi women. Oncol Lett. 3:875–878. 2012.PubMed/NCBI | |
|
Zaravinos A: An updated overview of HPV-associated head and neck carcinomas. Oncotarget. 5:3956–3969. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Petit CS, Besnier L, Morel E, Rousset M and Thenet S: Roles of the cellular prion protein in the regulation of cell-cell junctions and barrier function. Tissue Barriers. 1:e243772013. View Article : Google Scholar | |
|
Roucou X: Regulation of PrPC signaling and processing by dimerization. Front Cell Dev Biol. 2:572014. View Article : Google Scholar | |
|
Martin-Lannerée S, Hirsch TZ, Hernandez-Rapp J, Halliez S, Vilotte JL, Launay JM and Mouillet-Richard S: PrPC from stem cells to cancer. Front Cell Dev Biol. 2:552014. | |
|
Cheng Y, Li Y, Liu D, Zhang R and Zhang J: miR-137 effects on gastric carcinogenesis are mediated by targeting Cox-2-activated PI3K/AKT signaling pathway. FEBS Lett. 588:3274–3281. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Xue P, Yang X, Liu Y, Xiong C and Ruan J: A novel compound RY10-4 downregulates P-glycoprotein expression and reverses multidrug-resistant phenotype in human breast cancer MCF-7/ADR cells. Biomed Pharmacother. 68:1049–1056. 2014. View Article : Google Scholar : PubMed/NCBI |
