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. 2014 Feb;21(1):e67–e74. doi: 10.3747/co.21.1595

Reduced expression of members of the mhc-i antigen processing machinery in ethnic Uighur women with cervical cancer in the Xinjiang region of China

A Haimiti *, Y Hailiman †, A Gulina ‡, J Du §, Z Hao §, XL Rong *, A Zainuer ‡, W Qin *, S Lalai †,✉
PMCID: PMC3921050  PMID: 24523623

Abstract

Objective

Cervical cancer is a major cause of mortality in Uighur women compared with Han women in the Xinjiang region of China. Although a reduction in the class i major histocompatibility complex (mhc-i) antigen processing machinery (apm) is associated with the development of cervical cancer, the mhc-i apm has not been studied in this particular group of women, who have the highest incidence rate of cervical cancer in China.

Study Design

We used immunohistochemical staining and polymerase chain reaction amplification of viral dna from infection with the human papilloma virus (hpv) to study the expression of members of the mhc-i apm in cervical cancer sections collected from Uighur and Han women and in cervicitis samples from age-matched counterparts.

Results

Expression of the molecules of interest was compared between two ethnic groups, and expression of transporter associated with antigen processing 1 and 2, heat shock protein 90, and calnexin were found to be reduced even more significantly in Han women with cervical cancer than in Uighur women with same disease. However, compared with Han women, Uighur women had a higher rate of infection with hpv 16.

Conclusions

The mhc-i apm were reduced in cervical cancer, with heterogeneity in the two ethnic groups. The reduction was more pronounced in Han women, who less frequently had hpv 16 infection, suggesting possible differences in the roles of members of the mhc-i apm and in the mechanisms of cervical cancer development in these two ethnic groups despite residence in the same region of China.

Keywords: tap-1, tap-2, β2-microglobulin, Hsp70, calnexin, Hsp90, Grp94, hpv 16

1. INTRODUCTION

Cervical cancer is the second most common malignant tumour in women worldwide, with 500 thousand new cases and 275 thousand deaths occurring each year 1. The cervical cancer incidence rate is very high in China, and in particular, the Uighur women who live in southern region of Xinjiang Province, China, have the highest morbidity and mortality from cervical cancer in the country, even when compared with women of other ethnicities from the same geographic area. Cervical cancer is a major cause of death in Uighur women of this region 2. Furthermore, cervical cancer tends to develop in Uighur women at younger ages. The high rate of cervical cancer development in these ethnic women is probably at least partly attributable to a high prevalence of infection with human papilloma virus (hpv). The overall hpv infection rate is 459 per 100,000, and the high-risk genotype hpv 16 is the most dominant virus type, being shown to be present in 77.6%–82.6% of Uighur women with cervical cancer 2,3.

Immunity mediated by T-cells, especially CD8+ cytotoxic T lymphocytes (ctls), plays a critical role in protecting against the development of cervical cancer. However, tumour cells, including those in cervical cancer, have developed several mechanisms to escape ctl-mediated immune protection 4. Loss of expression of human leukocyte antigen class i molecules and components of the class i major histocompatibility complex (mhc-i) antigen processing machinery (apm) is of particular importance, because reductions in those molecules provide a mechanistic pathway for tumour cells to evade ctl-mediated immunity 5. The apm is responsible for presentation of tumour antigenic peptides by mhc-i molecules. After processing by cytoplasmic immunoproteasomes, tumour antigenic peptides are transported from the cytoplasm to the endoplasmic reticulum by transporter associated with antigen processing (tap) proteins tap-1 and tap-2. The peptides are then cut into segments 8–9 amino acids in length by endoplasmic reticulum aminopeptidase associated with antigen presentation 1, and loaded into empty mhc-i molecules with the help of tapasin and the chaperone molecules calnexin (cnx), calreticulin, and erp57 6–9.

Previous studies demonstrated varying levels of reduction and even complete loss of apm components in human malignancies, including cervical cancer. Reduction of these molecules has been associated with poor prognosis 10–12. Infection with hpv is a major risk factor associated with cervical cancer development, and persistent infection with hpv may lead to reduced ctl-mediated immunity against tumour development 13. However, the exact role of reduced expression of apm molecules in hpv-induced cervical carcinogenesis remains elusive, and the mechanisms related to the high incidence of cervical cancer in Uighur women in Xinjiang remain to be explored. We investigated the expression of major mhc-i–associated apm components such as tap-1, tap-2, 70-kDa heat shock protein (Hsp70), β2-microglobulin (β2M), cnx, heat shock protein 90 (Hsp90), and heat shock protein 90 kDa beta (Grp94) in a large number of cervical cancer specimens collected from Uighur and Han women of the Xinjiang region.

2. METHODS

2.1. Patients and Tissue Samples

We collected cervical tissue samples from 142 cervical cancer patients (99 of Uighur ethnicity, 43 of Han ethnicity). As a control, we also collected cervical tissue sections from 87 patients with cervicitis (36 of Uighur ethnicity, 51 of Han ethnicity) during clinic visits between 2002 and 2007 to the First Affiliated Hospital of Xinjiang Medical University, Urumqi, and the First People’s Hospital of Kashi District, Xinjiang, China. All patients were residents of the region and had not received preoperative radiotherapy or chemotherapy at the time of sample collection.

Mean age of the Uighur women was 47 years (range: 23–70 years), and mean age of the Han women was 38 years (range: 28–65 years). The tissues were formalin-fixed and paraffin-embedded, and the diagnosis was histologically confirmed by experienced pathologists from the departments of pathology at the respective hospitals. The use of clinical materials for this study was approved by the Institutional Review Board of Xinjiang Medical University, following the guidelines of the Chinese Federation of Medical Research Associations.

2.2. Reagents

The rabbit polyclonal antibodies used in this study were anti-β2M (DakoCytomation, Glostrup, Denmark), anti-cnx (Proteintech Group, Chicago, IL), anti–tap-1 (Abgent, San Diego, CA, U.S.A.), anti-Hsp70 and anti-Hsp90 (Cell Signaling Technology, Danvers, MA, U.S.A.), anti-Grp94 (Lab Vision Corporation, Fremont, CA, U.S.A.), and anti–tap-2 (Atlas Antibodies AB, Stockholm, Sweden). Histostain-Plus kits were obtained from Jingmei Biotech Corporation (Shenzhen, China).

2.3. Immunohistochemical Staining

Immunohistochemical staining was performed as previously described 14. Briefly, 4-μm sections were dewaxed in xylol and methanol, and endogenous peroxidases were blocked for 15 minutes in methanol with 3% H2O2. Antigenic epitopes were unmasked by microwave heating at 98.5°C for 15 minutes in 0.01 mol/L citrate-buffered solution (pH 6.0), and cooled to room temperature in the same solution for 30 minutes. The slides were rinsed in phosphate-buffered saline (pbs) with 0.05% polysorbate 20 surfactant for 20 minutes. For immunohistochemical detection of proteins, the slides were pre-incubated with 10% normal goat serum in pbs and then incubated with the respective antibodies diluted in pbs with 1% goat serum to an optimal concentration based on pilot experiments. After 30 minutes’ incubation at room temperature, the slides were washed with pbs containing polysorbate 20 surfactant and then incubated with biotinylated goat anti-rabbit antibody. Incubation with streptavidin-labelled horseradish peroxidase followed. Reactivity was visualized with diaminobenzidine (all chemicals from Jingmei Biotech Corporation) for 5 minutes at room temperature. The slides were then counterstained with hematoxylin and mounted in Permount Mounting Medium (Thermo Fisher Scientific, Waltham, MA, U.S.A.). Slides with known positive tissue sections were used as positive controls, and slides stained with isotype-matched immunoglobulin molecules were used as negative controls.

2.4. Evaluation of Immunohistochemistry

Because tap-1, tap-2, Hsp70, β2M, cnx, Hsp90, and Grp94 are expressed in the cervical epithelial cell cytoplasm, the appearance under the microscope of brown immunohistochemical staining in the cytoplasm of cells was determined to be positive for the target protein. Positive samples were further graded into four levels based on the area occupied by cells positive for the target antigen: less than 5% was graded as negative; 5%–25%, as weakly positive (+); 26%–50%, as positive (++); 51%–75%, as strongly positive (+++); and more than 75%, as very strongly positive (++++). Two pathologists read the slides back-to-back in a blind manner.

2.5. DNA Extraction

Depending on the size of the tissue samples, 5–20 tissue sections 10-μm2 in size were collected in 1.5 mL Eppendorf tubes, and dna was extracted using the QIAamp DNA Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s directions. The quality and quantity of extracted dna samples were determined by optical density measurements at 260 nm and 280 nm.

2.6. Detection of Viral Infection

The quality of dna samples was validated by amplification of a 110-bp fragment of the housekeeping HBB gene. Infection with hpv was examined by polymerase chain reaction (pcr) amplification of hpv-specific dna sequences in the samples extracted from the paraffin-embedded cervical tissues. This procedure used a universal hpv primer pair (“consensus primer”) and the primer pairs specific for high-risk hpv 16 and hpv 18.

The sequences of primer sets for hpv 16 (with a 96-bp product size) and hpv 18 (with a 115-bp product size) were these:

  • Forward 5′-GGTCGGTGGACCGGTCGATG-3′ and reverse 5′-GCAATGTAGGTGTATCTCCA-3′ (hpv 16)

  • Forward 5′-CCTTGGACGTAAATTTTTGG-3′ and reverse 5′-CACGCACACGCTTGGCAGGT-3′ (hpv 18)

The pcr was performed in a 5 0-μL reaction volume containing 500 ng dna, 1.5 U TaKaRa Ex Taq Polymerase (Millipore Corporation, Billerica, MA, U.S.A.), dNTP mix (Life Technologies, Beijing, PR China) at 100 μmol/L, and 2 μL of each primer (20 pmol/mL). The cycling conditions were denaturation at 95°C for 3 minutes, followed by 40 cycles of denaturation at 95°C for 15 seconds, primer annealing at 59°C (hpv 18) or 60°C (hpv 16) for 20 seconds, and extension at 72°C for 25 seconds, with a final extension at 72°C for 7 minutes 15. The cycling protocol for the Gp consensus primers (Gp5 and Gp6) was 40 cycles, which included denaturation at 94°C for 30 seconds, primer annealing at 45°C for 30 seconds, and extension at 72°C for 30 seconds 16. All reagents were obtained from Takara Biotechnology (Dalian, China).

For analysis of pcr results, 5 μL of each pcr reaction product was resolved by electrophoresis in 1.5% agarose gel (Agarose B: BBI-Biotech, Berlin, Germany), and the images were recorded using a Gel Doc 2000 system (BioRad, Hercules, CA, U.S.A.).

2.7. Statistical Analysis

The statistical analysis was performed using the SPSS software application (version 13.0: SPSS, Chicago, IL, U.S.A.). Data were evaluated using the logrank and chi-square tests. The level of significance was set at p < 0.05. Correlations between the categorized biomarkers were examined. A chi-square test was performed for each ethnic group and was used to compare protein expression in the presence or absence of cervical lesions.

3. RESULTS

Figure 1 shows a representative result for all members of the apm associated with mhc-i antigen presentation and processing. The immunohistochemical streptavidin–peroxidase method successfully visualized the presence of target proteins in the tissue sections from both cervicitis and cervical cancer patients. The positive cells in the cervicitis and cervical cancer samples were stained brown in cytoplasm, and the cervical epithelial cells were stained at the base or diffusely. Most cells were stained in the cytoplasm; a few cells were also stained in the cell nuclei.

FIGURE 1.

FIGURE 1

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Expression of components of the class i major histocompatibility complex (mhc-i) antigen processing machinery (apm) in cervical tissues from patients with cancer and cervicitis (200× original magnification).

Because of sample loses during the staining process, results were obtained for 111 of 142 cervical cancer tissue sections and for 68 of 87 cervicitis lesions (Table i). Overall, our results demonstrated that, regardless of ethnicity, positive expression of tap-1, tap-2, β2M, and Hsp90 were significantly reduced in cervical tissue sections from patients with cervical cancer compared with sections from patients with cervicitis. The expression of the remaining antimicrobial peptides (Hsp70, cnx, and Grp94) were slightly more reduced in in cervical cancer lesions than in cervicitis, but the differences were nonsignificant. The reduction in tap-1, tap-2, Hsp90, and cnx were even more pronounced in cervical cancer sections from Han women than in those from their Uighur counterparts. However, β2M was more significantly reduced in Uighur women with cervical cancer than in their Han counterparts, suggesting differences in the pattern of change to those molecules between the two ethnic groups.

TABLE I.

Expression of class i major histocompatibility complex antigen processing machinery components in cervicitis and cervical cancer sections from Uighur and Han women

Pathologic type Pts (n) Patients [n (%)] positive for
β2M Tap1 Tap2 Hsp70 Hsp90 Cnx Grp94 hpv 16
Cervicitis 68 64 (94.12) 55 (80.88) 66 (97.06) 50 (73.53) 67 (98.53) 64 (94.12) 64 (94.12) 8 (11.76)
  Han 37 33 (89.19) 27 (72.97) 35 (94.59) 26 (70.27) 36 (97.30) 33 (89.19) 33 (89.20) 1 (2.70)
  Uighur 31 31 (100) 28 (90.32) 31 (100) 24 (77.42) 31 (100) 31 (100) 31 (100) 7 (22.58)
Cervical cancer 111 69 (62.16)a 56 (50.45)a 68 (61.62)a 86 (77.48) 65 (58.56)a 96 (86.49) 91 (81.98) 38 (34.23)a
  Han 35 29 (82.86)b 11 (31.43)b 15 (42.86)b 23 (65.71) 12 (34.29)b 24 (68.57)b 27 (77.14)a 3 (8.57)b
  Uighur 76 40 (52.63) 45 (59.21) 53 (69.74) 63 (82.89) 53 (69.74) 72 (94.74) 64 (84.21) 35 (46.05)
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a

p < 0.05, cervical cancer versus cervicitis.

b

p < 0.05, Han versus Uighur women with cervical cancer.

β2M = β2-microglobin; Tap1 = transporter associated with antigen processing 1; Tap2 = transporter associated with antigen processing 2; Hsp70 = heat-shock protein 70; Hsp90 = heat-shock protein 90; Cnx = calnexin; Grp94 = glucose regulated protein 94; hpv = human papilloma virus.

We observed positive correlations between the expressions of tap-2 and β2M in Han women with squamous cell cervical cancer (r = 0.433, p < 0.05) and cervicitis (r = 0.687, p < 0.05). Other positive correlations were observed between the expressions of Hsp70 and cnx in Han women with squamous cell cervical cancer (r = 0.419, p < 0.05) and between the expressions of tap-1 and β2M in Uighur women with squamous cell cervical cancer (r = 0.339, p < 0.05).

As shown in Figure 2, we successfully amplified hpv 16 and hpv 18 genes from cervical lesions. The results of that experiment, shown in Table i, demonstrate that hpv 16 was present i n 35 of 76 cervical cancer samples (46.05%) from Uighur women. In contrast, only 3 of 35 cervical cancer samples (8.57%) from Han women were positive for hpv 16. Thus, in the same geographic region, Uighur women with cervical cancer were infected with hpv 16 significantly more frequently than were their Han counterparts. The same imbalance was true for the hpv 16 infection rate: cervical samples from Uighur women with cervicitis showed a hpv 16 infection rate that was higher by a factor of 10 than that in Han women with cervicitis. Overall, the hpv 16 infection rate was significantly higher in women with cervical cancer than in those with cervicitis. However, the hpv 18 infection rate was very low: just 7 of 68 cervical cancer tissue samples were positive for hpv 18.

FIGURE 2.

FIGURE 2

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Polymerase chain reaction (pcr) amplification of human papilloma virus (hpv) 16 and hpv 18 from dna samples isolated from cervical cancer lesions. From left to right, the pcr bands show marker and samples that are negative, positive for hpv 16, and positive for hpv 18.

We also analyzed the relationship between changes in the expression of apm components and infection with hpv 16 in cervical cancer samples. In Uighur women with cervical cancer, we observed a positive correlation between the expressions of β2M and hpv 16 (p = 0.021, r = 0.162), between Hsp90 and hpv 16 (p = 0.000, r = 0.483), and between Grp94 and hpv 16 (p = 0.009, r = 0.765). To our surprise, although Han women with cervical cancer were infected with either hpv 16 or hpv 18 less frequently than were their Uighur counterparts, expressions of tap-1, tap-2, Hsp90, and cnx were significantly lower in those women than in Uighur women.

4. DISCUSSION

The results from our analysis of apm components of mhc-i antigen presentation in a relatively large sample of cervical cancer and cervicitis patients demonstrated that the expressions of mhc-i–associated apm components were lower in cervical tissues from cervical cancer patients than in samples from cervicitis patients and that there were significant differences in the levels of expression of tap-1 and tap-2 between women of different ethnicities from the same geographic region. In both cervicitis and cervical cancer, hpv 16 was the dominant type of hpv infecting Uighur women, whose infection rate was significantly higher than that of Han women with same disease.

Previous studies showed that the expressions of tap-1 and tap-2 were lower in 72% of patients (21 of 29) with cervical cancer 17. The rate of tap-1 disappearance in cervical cancer is about 48.64% 18, and decreased tap protein expression was correlated with lesser differentiation of cancer cells. In accord with previous reports, our study also demonstrated that expressions of tap-1 and tap-2 proteins were lower in cervical cancer than in cervicitis in women of both ethnicities, and that expressions of β2M, Hsp90, and cnx were also reduced in cervical cancer tissues compared with cervicitis tissues. The reductions in these proteins were significantly more pronounced in Han women with cervical cancer than in Uighur women with same disease, suggesting that a decrease in tap proteins might be a common feature in cervical cancer patients regardless of ethnicity. The decline in tap proteins might possibly lead to decreased expression of class i mhc molecules on cancer cells, which might in turn serve as an effective way for cancer cells to escape immune surveillance.

We observed a positive correlation between the expressions of tap-2 and β2M in Han women with squamous cell cervical cancer (r = 0.433, p < 0.05). However, in Uighur women, we observed a positive correlation between the expressions of β2M and tap-1 in squamous cell cervical cancer (r = 0.339, p < 0.05), suggesting a similar pattern of decline of β2M and tap proteins in cancer patients. Those findings might imply that a decline in tap proteins in cancer cells leads to reduced antigenic peptide loading to mhc-i molecules and therefore to lesser expression of β2M. Hence, it is reasonable to speculate that the reduction in β2M may be secondary to the reduction in tap proteins in cervical cancer patients.

An essential part of the mhc-i molecule, β2M is indispensable for stable expression and efficient antigenic peptide presentation to ctl cells 19,20. It can facilitate the binding of antigenic peptides to cell-surface mhc-i 21,22 and is therefore required for initiation of a normal immune response. The occurrence and development of tumours is tightly associated with β2M, and the combination of β2M with other tumour markers might increase the sensitivity of cancer diagnosis 23. Studies from Western countries have demonstrated reduced β2M in patients with pre-malignant cervical lesions 24,25. Another study also demonstrated that the expressions of tap-1, tap-2, cnx, and β2M were reduced in cancer lesions 26. In the present study, the positive expression rate of β2M in cervical cancer (62.16%) was significantly lower than that in cervicitis (94.12%, p < 0.05), although β2M was not reduced in Han women with cervical cancer compared with Han women having cervicitis. However, the expression of β2M in Uighur patients with cervical cancer was lower—or even lost—compared with such expression in cervicitis, suggesting a disease-specific reduction of β2M, at least in Uighur women.

The heat shock proteins are involved in mhc-i and mhc-ii restricted antigen presentation and stimulation of CD8+ ctls 27,28, and those proteins might be able to be used as vaccines for adjuvant cancer therapy. The heat shock proteins are widely associated with cancer cell cycle regulation, proliferation, apoptosis, differentiation, multidrug resistance, tumour immunity, and immunity against viral infection 29,30. Chen et al. 31 showed that the expression of Hsp70 was higher in cervical cancer patients than in normal control subjects. Studies by Guo et al. 32 indicated that the expression of Hsp70 was associated with pathologic grade, clinical stage, and metastasis to lymph nodes in cervical cancer. Other studies have also demonstrated a gradually elevated expression of Hsp70 in cervical cancer cells with high, moderate, and poor differentiation, suggesting that elevated expression of Hsp70 is associated with active tumour growth, poor differentiation, and greater malignancy. However, we did not see any differences in the expression of Hsp70 in cervical cancer lesions compared with cervicitis in either ethnic group. That observation might be a result of differences in the reagents and clinical samples between previous studies and our study. An investigation by Zhao et al. 33 indicated that the expression of Hsp90 was significantly higher in invasive carcinoma of cervix and cervical intraepithelial neoplasia than it was in cervicitis and normal cervix. The increase in the expression of Hsp90 in cervical cancer might be attributable to increased demand for heat shock protein in cancer cells to regulate and stabilize abnormal growth because of uncontrolled cell growth and increased cell metabolism. Another possibility is that increased expression of Hsp90 may act as cell-surface marker for escaping from immune surveillance, thus facilitating cancer development or affecting the function of cancer killers, such as natural killer cells 34. However, our study did not support that notion: The expression of Hsp90 was lower in cervical cancer samples than in cervicitis in both ethnic groups, and we could not make any reasonable speculation about the discrepancies between earlier reports and our findings. However, we did observe a positive correlation in the expression levels of Hsp90 and Hsp70 in cervical cancers from Uighur women (r = 0.265, p < 0.05), an observation that might be a result of a similar regulatory mechanism in cancer cells, because those two proteins belong to the same family.

Calcium binding protein in the endoplasmic reticulum, cnx, is a molecular chaperone that helps with the correct folding of mhc class i molecules to form a functional dimer 35,36. Reduced expression or absence of cnx may therefore lead to downregulation of mhc-i expression 37,38. A study by Ritz et al. 26 showed a significant reduction of cnx in tissues from cervical cancer patients compared with normal cervical tissues. Our results confirmed that finding, with reduced expression of cnx in cervical cancer than in cervicitis in women of both ethnicities. Expression of cnx in Uighur women was higher than that in Han women in both disease groups, and the difference was statistically significant (p < 0.05). Pronounced reduction of cnx in cervical cancer in Han women compared with their Uighur counterparts might play a role, at least in part, in the more pronounced reduction of other components of the apm in Han women with cervical cancer.

The molecular chaperone Grp94 (“glucose-regulated protein”) is a more abundant protein component of the normal cellular endoplasmic reticulum. It helps with correct folding and assembly of proteins in the cell. The literature documents the initiation of a stress reaction in glucose metabolism in cancer cells with the start of tumour growth 39,40, and therefore Grp94 is associated with tumourigenesis and tumour growth. In studies that mimicked cutting of the blood supply in solid tumours to reduce glucose levels in cancer tissues, the expression of Grp94 increased by a factor of 9 from the expression level found in normal breast epithelial cells. However, in our study, expression of Grp94 did not increase in cervical cancer compared with cervicitis; however, expression levels were reduced more significantly in Han women with cervical cancer than in Uighur women with the same disease. Expression of Grp94 might be associated with growth retardation and differentiation of tumour cells 41.

The different changes of β2M and Grp94 in the two ethnic groups of women with cervical cancer suggest that expression of some of the members of the mhc-i apm in cervicitis and cervical cancer may differ depending on ethnicity.

According to previous reports, the rate of infection with hpv 16 in cervical cancer patients in other countries is 54.6% 42; it is 60.0% 43 and 63.4% 44 in cervical cancer patients from Inner Mongolia in China; and in Uighur women with cervical cancer, it ranges from 61.6% to 84.61% 45,46. In accord with those findings, our study showed that the rate of infection with hpv 16 in Uighur women with cervical cancer in Xinjiang was 58%–62% and that their rate is significantly higher than the rate in Han women with cervical cancer from the same region. The difference in rates of hpv 16 infection in these two ethnic groups might be a result of differences in ethnic culture and lifestyle.

Only 7 of our 68 Uighur cervical cancer patients were positive for hpv 18 infection, and none of our 35 Han cervical cancer patients was positive for hpv 18. That finding might be related to the fact that all the cervical cancer specimens collected were squamous cell carcinoma 47. The frequency of concurrent infection with both hpv 16 and hpv 18 was higher in Uighur women with cervical cancer 48.

5. CONCLUSIONS

Our study demonstrated reduced expression of mhc-i antigen presentation–associated molecules in cervical cancer lesions. The level of the reduction was heterogeneous and, for some molecules, showed ethnic specificity. The mechanisms underlying the reduced expression of these proteins, with differences between ethnic groups, and the exceptionally high hpv 16 infection rate in Uighur women with cervical cancer (with less pronounced reduction of apm members) and their association with cervical cancer need to be addressed in future studies.

6. ACKNOWLEDGMENTS

This research was supported by the National Natural Science Foundation of the Peoples’ Republic of China (no. 30460046). We thank Buka Samten for useful discussion and critical reading of the manuscript.

7. CONFLICT OF INTEREST DISCLOSURES

The authors declare that they have no financial conflicts of interest.

8. REFERENCES

  • 1.Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108. doi: 10.3322/canjclin.55.2.74. [DOI] [PubMed] [Google Scholar]
  • 2.Jiang S, Wang T, Tu S. Investigation of cervical cancer in Cele county of Xinjiang, China [Chinese] Chin J Pract Gynecol Obstet. 2006;22:379–81. [Google Scholar]
  • 3.Li T, Gulina K, Wang T, et al. A Study on the prevention and therapy of carcinoma of the cervix in Xaptul Township, Jashi County, Xinjiang [Chinese] J Xinjiang Med Univ. 1996;19:199–203. [Google Scholar]
  • 4.Tindle RW. Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer. 2002;2:59–65. doi: 10.1038/nrc700. [DOI] [PubMed] [Google Scholar]
  • 5.Seliger B, Cabrera T, Garrido F, Ferrone S. hla class i antigen abnormalities and immune escape by malignant cells. Semin Cancer Biol. 2002;12:3–13. doi: 10.1006/scbi.2001.0404. [DOI] [PubMed] [Google Scholar]
  • 6.York IA, Rock KL. Antigen processing and presentation by the class i major histocompatibility complex. Annu Rev Immunol. 1996;14:369–96. doi: 10.1146/annurev.immunol.14.1.369. [DOI] [PubMed] [Google Scholar]
  • 7.Gromme M, Neefjes J. Antigen degradation or presentation by mhc class i molecules via classical and non-classical pathways. Mol Immunol. 2002;39:181–202. doi: 10.1016/S0161-5890(02)00101-3. [DOI] [PubMed] [Google Scholar]
  • 8.Van Kaer L. Major histocompatibility complex class i–restricted antigen processing and presentation. Tissue Antigens. 2002;60:1–9. doi: 10.1034/j.1399-0039.2002.600101.x. [DOI] [PubMed] [Google Scholar]
  • 9.York IA, Chang SC, Saric T, et al. The er aminopeptidase erap1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues. Nat Immunol. 2002;3:1177–84. doi: 10.1038/ni860. [DOI] [PubMed] [Google Scholar]
  • 10.Meissner M, Reichert TE, Kunkel M, et al. Defects in the human leukocyte antigen class i antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res. 2005;11:2552–60. doi: 10.1158/1078-0432.CCR-04-2146. [DOI] [PubMed] [Google Scholar]
  • 11.Facoetti A, Nano R, Zelini P, et al. Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumours. Clin Cancer Res. 2005;11:8304–11. doi: 10.1158/1078-0432.CCR-04-2588. [DOI] [PubMed] [Google Scholar]
  • 12.Mehta AM, Jordanova ES, Kenter GG, Ferrone S, Fleuren GJ. Association of antigen processing machinery and hla class i defects with clinicopathological outcome in cervical carcinoma. Cancer Immunol Immunother. 2008;57:197–206. doi: 10.1007/s00262-007-0362-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Campo MS, Graham SV, Cortese MS, et al. hpv-16 E5 downregulates expression of surface hla class i and reduces recognition by CD8 T cells. Virology. 2010;407:137–42. doi: 10.1016/j.virol.2010.07.044. [DOI] [PubMed] [Google Scholar]
  • 14.Dang SS. Precision Code of Common Medical Test Technology [Mandarin] Xi’An, PR China: World Publishing Corporation; 2004. pp. 43–44. [Google Scholar]
  • 15.Biedermann K, Dandachi N, Trattner M, et al. Comparison of real-time pcr signal-amplified in situ hybridization and conventional pcr for detection and quantification of human papillomavirus in archival cervical cancer tissue. J Clin Microbiol. 2004;42:3758–65. doi: 10.1128/JCM.42.8.3758-3765.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Husnjak K, Grce M, Magdić L, Pavelić K. Comparison of five different polymerase chain reaction methods for detection of human papillomavirus in cervical cell specimens. J Virol Methods. 2000;88:125–34. doi: 10.1016/S0166-0934(00)00194-4. [DOI] [PubMed] [Google Scholar]
  • 17.Cresswell AC, Sisley K, Laws D, Parsons MA, Rennie IG, Murray AK. Reduced expression of tap-1 and tap-2 in posterior uveal melanoma is associated with progression to metastatic disease. Melanoma Res. 2001;11:275–81. doi: 10.1097/00008390-200106000-00009. [DOI] [PubMed] [Google Scholar]
  • 18.Cromme FV, Airey J, Heemels MT, et al. Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of hla expression in cervical carcinomas. J Exp Med. 1994;179:335–40. doi: 10.1084/jem.179.1.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Kozlowski S, Takeshita T, Boehncke WH, et al. Excess beta 2 microglobulin promoting functional peptide association with purified soluble class i mhc molecules. Nature. 1991;349:74–7. doi: 10.1038/349074a0. [DOI] [PubMed] [Google Scholar]
  • 20.Otten GR, Bikoff E, Ribaudo RK, et al. Peptide and beta 2-microglobulin regulation of cell surface mhc class i conformation and expression. J Immunol. 1992;148:3723–32. [PubMed] [Google Scholar]
  • 21.Shields MJ, Assefi N, Hodgson W, Kim EJ, Ribaudo RK. Characterization of the interactions between mhc class i subunits: a systematic approach for the engineering of higher affinity variants of beta 2-microglobulin. J Immunol. 1998;160:2297–307. [PubMed] [Google Scholar]
  • 22.Shields MJ, Kubota R, Hodgson W, et al. The effect of human beta2-microglobulin on major histocompatibility complex i peptide loading and the engineering of a high affinity variant. Implications for peptide-based vaccines. J Biol Chem. 1998;273:28010–18. doi: 10.1074/jbc.273.43.28010. [DOI] [PubMed] [Google Scholar]
  • 23.Zheng WY, Yao LX, Lü WCH, et al. Value of combined test for ca-50, cea, afp and β2-mg in improving the detection rate of malignant tumors of digestive tract. Hebei Med. 1999;5:7–9. [Google Scholar]
  • 24.Tseleni–Balafouta S, Balafoutas AC, Paraskevakou H. Loss of beta 2 microglobulin from the surface of “dysplastic” and malignant epithelial cells of the uterine cervix [German] Zentralbl Gynakol. 1989;111:744–8. [PubMed] [Google Scholar]
  • 25.Petersen BL, Petersen CL, Braendstrup O, et al. Expression of beta 2-microglobulin by premalignant epithelium. APMIS. 1993;101:529–36. doi: 10.1111/j.1699-0463.1993.tb00142.x. [DOI] [PubMed] [Google Scholar]
  • 26.Ritz U, Momburg F, Pilch H, Huber C, Maeurer MJ, Seliger B. Deficient expression of components of the mhc class i antigen processing machinery in human cervical carcinoma. Int J Oncol. 2001;19:1211–20. doi: 10.3892/ijo.19.6.1211. [DOI] [PubMed] [Google Scholar]
  • 27.Mimnaugh EG, Xu W, Vos M, et al. Simultaneous inhibition of Hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. Mol Cancer Ther. 2004;3:551–66. [PubMed] [Google Scholar]
  • 28.Dressel R, Grzeszik C, Kreiss M, et al. Differential effect of acute and permanent heat shock protein 70 overexpression in tumor cells on lysability by cytotoxic T lymphocytes. Cancer Res. 2003;63:8212–20. [PubMed] [Google Scholar]
  • 29.Stebbing J, Gazzard B, Portsmouth S, et al. Disease-associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor. Blood. 2003;102:1806–14. doi: 10.1182/blood-2003-03-0891. [DOI] [PubMed] [Google Scholar]
  • 30.Florin L, Becker KA, Sapp C, et al. Nuclear translocation of papillomavirus minor capsid protein L2 requires Hsc70. J Virol. 2004;78:5546–53. doi: 10.1128/JVI.78.11.5546-5553.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Chen XM, Xia KD, Lin QA, Dong HY, Zhang LF. Study of expression of Hsp70, p53 and Bcl-2 in cervical cancer and their correlation [Chinese] China J Mod Med. 2005;15:253–5. [Google Scholar]
  • 32.Guo YH, Tian XY, Mi JQ, Xiong LL. Expression and significance of Hsp70 and Bcl-2 in cervical squamous cell cancer [Chinese] Shandong Med J. 2006;46:11–12. [Google Scholar]
  • 33.Zhao EF, Bao L, Liang L, Li D. Expressions of heat shock protein in cervical cancer and precancerosis [Chinese] Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2006;22:250–3. [PubMed] [Google Scholar]
  • 34.Qiao HH, Zhao M, Yuan XH, et al. Expression of heat shock protein 90α and its effect on the growth of tumor in mice [Chinese] Zhonghua Zhong Liu Za Zhi. 1999;21:19–22. [PubMed] [Google Scholar]
  • 35.Branza–Nichita N, Petrescu AJ, Dwek RA, Wormald MR, Platt FM, Petrescu SM. Tyrosinase folding and copper loading in vivo: a crucial role for calnexin and alpha-glucosidase ii. Biochem Biophys Res Commun. 1999;261:720–5. doi: 10.1006/bbrc.1999.1030. [DOI] [PubMed] [Google Scholar]
  • 36.Gassler N, Schnolzer M, Rohr C, et al. Expression of calnexin reflects paneth cell differentiation and function. Lab Invest. 2002;82:1647–59. doi: 10.1097/01.LAB.0000041709.42598.4A. [DOI] [PubMed] [Google Scholar]
  • 37.Matsui M, Machida S, Itani–Yohda T, Akatsuka T. Downregulation of the proteasome subunits, transporter, and antigen presentation in hepatocellular carcinoma, and their restoration by interferon gamma. J Gastroenterol Hepatol. 2002;17:897–907. doi: 10.1046/j.1440-1746.2002.02837.x. [DOI] [PubMed] [Google Scholar]
  • 38.Seliger B, Wollscheid U, Momburg F, Blankenstein T, Huber C. Characterization of the major histocompatibility complex class i deficiencies in B16 melanoma cells. Cancer Res. 2001;61:1095–9. [PubMed] [Google Scholar]
  • 39.Tomida A, Suzuki H, Kim HD, Tsuruo T. Glucose-regulated stresses cause decreased expression of cyclin D1 and hypophosphorylation of retinoblastoma protein in human cancer cells. Oncogene. 1996;13:2699–705. [PubMed] [Google Scholar]
  • 40.Cai JW, Henderson BW, Shen JW, Subjeck JR. Induction of glucose regulated proteins during growth of a murine tumor. J Cell Physiol. 1993;154:229–37. doi: 10.1002/jcp.1041540204. [DOI] [PubMed] [Google Scholar]
  • 41.Wu YD, Song JD. The expression of glucose regulated protein-94 in colorectal carcinoma cells treated by sodium butyrate. Cell Res. 2000;10:115–25. doi: 10.1038/sj.cr.7290041. [DOI] [PubMed] [Google Scholar]
  • 42.Muñoz N, Bosch FX, de Sanjosé S, et al. on behalf of the International Agency for Research on Cancer Multicenter Cervical Cancer Study Group Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–27. doi: 10.1056/NEJMoa021641. [DOI] [PubMed] [Google Scholar]
  • 43.Wang JM, Qin WB, Yan XL, Sui TL. Relationship between cervical cancer and subtypes of human papilloma virus in Erdos region [Chinese] Inner Mongolia Med J. 2005;37:297–9. [Google Scholar]
  • 44.Xie J, Qiao HZH, Wang L, Ma X. Detection of human papilloma virus by polymerase chain reaction in cervical cancer in Inner Mongolia [Chinese] Inner Mongolia Med J. 2003;37:299–302. [Google Scholar]
  • 45.Guzalinur A, Peng Z, Liu SL. Detection of human papillomavirus dna in cervical carcinoma in Uygur women from Hotan region of Xinjiang Uygur Autonomy Region [Chinese] Sichuan J Cancer Control. 2001;14:77–80. [Google Scholar]
  • 46.Suzuk L, Noffsinger AE, Ali M, Fenoglio–Preiser CM. A high frequency of human papilloma virus (hpv) dna type 16 in biopsies of cervical squamous cell neoplasia of Uygur women. Int J Surg Pathol. 1997;4:219–25. doi: 10.1177/106689699700400404. [DOI] [Google Scholar]
  • 47.Arends MJ, Donaldson YK, Duvall E, Wyllie AH, Bird CC. Human papillomavirus type 18 associates with more advanced cervical neoplasia than human papillomavirus type 16. Hum Pathol. 1993;24:432–7. doi: 10.1016/0046-8177(93)90093-V. [DOI] [PubMed] [Google Scholar]
  • 48.Abudulimu H, Maimaiti M, Suzuke L. Analysis of HPV16E6 oncogene mutation in cervical lesions in Xinjiang area. Chin J Clin Exp Pathol. 2009;25:513–18. [Google Scholar]

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