Open Access

Correlation between p38 mitogen-activated protein kinase and human telomerase reverse transcriptase in sarcomas

  • Toshihiro Matsuo1, 2Email author,
  • Shoji Shimose2,
  • Tadahiko Kubo2,
  • Jun Fujimori2,
  • Yuji Yasunaga3,
  • Takashi Sugita1 and
  • Mitsuo Ochi2
Contributed equally
Journal of Experimental & Clinical Cancer Research201231:5

DOI: 10.1186/1756-9966-31-5

Received: 6 December 2011

Accepted: 16 January 2012

Published: 16 January 2012

Abstract

Background

One of the major components of telomerase is the human telomerase reverse transcriptase (hTERT) as the catalytic protein. hTERT mRNA expression are reported to be associated with prognosis and tumor progression in several sarcomas. However, there is no clear understanding of the mechanisms of hTERT in human sarcomas. Recent studies have suggested that signals transmitted through p38 mitogen-activated protein kinase (MAPK) can increase or decrease hTERT transcription in human cells. The purpose of this study was to analyse the correlation between p38 MAPK and hTERT in sarcoma samples.

Methods

We investigated 36 soft tissue malignant fibrous histiocytomas (MFH), 24 liposarcomas (LS) and 9 bone MFH samples for hTERT and p38 MAPK expression. Quantitative detection of hTERT and p38 MAPK was performed by RT-PCR.

Results

There was a significant positive correlation between the values of hTERT and p38 MAPK in all samples (r = 0.445, p = 0.0001), soft tissue MFH (r = 0.352, p = 0.0352), LS (r = 0.704, p = 0.0001) and bone MFH samples (r = 0.802, p = 0.0093). Patients who had a higher than average expression of p38 MAPK had a significantly worse prognosis than other patients (p = 0.0036).

Conclusions

p38 MAPK may play a role in up-regulation of hTERT, and therefore, p38 MAPK may be a useful marker in the assessment of hTERT and patients' prognosis in sarcomas.

Keywords

p38 mitogen-activated protein kinase human telomerase reverse transcriptase malignant fibrous histiocytoma liposarcoma

Background

Telomerase, an enzyme related to cellular immortality, stabilizes telomere length by adding DNA repeats onto telomere ends [1, 2]. Many studies have revealed that telomerase activity is expressed in many different types of carcinomas, detected in more than 85% of the human carcinoma samples, and it has been found to be useful as a prognostic indicator [35]. Telomerase activity is mainly regulated by human telomerase reverse transcriptase (hTERT), which is the catalytic subunit of telomerase [6, 7]. Also, hTERT has been significantly detected in many types of sarcoma samples, and previous reports have indicated that hTERT expression is associated with tumor aggressiveness, feature and clinical outcome in sarcomas [814]. Therefore, hTERT may play an important role in telomere maintenance mechanisms in human sarcomas. However, it is notable that thus far, there has been no clear understanding of the mechanisms of hTERT expression especially in sarcomas. p38 is a mitogen-activated protein kinase (MAPK) activated by phosphorylation on serine/threonine residue when cells are exposed to cellular stress, and has a wide variety of biological functions [1517]. Recent studies have suggested that signals transmitted through MAP kinase can increase or decrease hTERT transcription in response to various stimuli, depending on the downstream mediators [1822]. This study was undertaken to analyze the clinical significance of p38 MAPK and hTERT expression in primary tumor samples from soft tissue malignant fibrous histiocytomas (MFH), liposarcomas (LS) and bone MFH patients. In addition, with the broader aim of discovering regulation factors of hTERT in sarcomas, we investigated whether there is a correlation between hTERT and p38 MAPK.

Methods

Patients and tumor samples

A total of 69 (36 soft tissue MFHs, 24 LSs and 9 bone MFHs) sarcoma samples were obtained at the time of surgery, were immediately frozen and stored at -80°C until commencement of our study. Summarized clinical data at the time of last observation are shown in Tables 1, 2 and 3. All patients with these sarcomas were treated with tumor resection and/or chemotherapy between 1988 and 2005. We performed brachytherapy or external radiation therapy following conservative surgery for all soft tissue sarcoma patients who received marginal resection. Chemotherapy comprised of multiagent systemic chemotherapy in metastatic patients. High dose ifosfamide, doxorubicin and/or cisplatin were used. We collected all primary tumor samples by tumor resection or biopsy, and no patients had undergone chemotherapy before surgical specimens were collected. The study was approved by our institutional review board (Dai eki 133, and 263).
Table 1

Data in 36 patients with soft tissue MFH

Age (Yrs)

Gender

Site

Histol. Type

Prognosis

Period (mos.)

hTERT

p38

53

Male

thigh

stori-pleo

DOD

12

28.4

0

48

Male

thigh

myxoid

NED

80

1564.5

0

76

Female

thigh

stori-pleo

DOD

22

2365

8.7

54

Male

thigh

stori-pleo

DOD

12

978.4

6.1

49

Male

upper arm

stori-pleo

DOD

18

22

2.8

63

Female

axillary

myxoid

CDF

28

383.4

4.5

82

Male

thigh

stori-pleo

CDF

80

181.9

3.3

66

Female

thigh

stori-pleo

CDF

60

133.2

0

75

Male

thigh

stori-pleo

NED

35

1986.5

2.8

45

Female

inguinal

myxoid

CDF

27

8.5

0.3

78

Female

thigh

stori-pleo

DOD

9

8.9

5.2

35

Male

thigh

stori-pleo

CDF

52

1.9

2.1

81

Male

thigh

stori-pleo

CDF

26

0

0

84

Male

buttock

stori-pleo

CDF

26

45.9

10

57

Female

shoulder

stori-pleo

CDF

62

158.3

36.2

76

Female

thigh

stori-pleo

DOD

6

196.8

50.1

75

Male

thigh

stori-pleo

DOD

10

147.3

15.6

57

Male

thigh

stori-pleo

CDF

94

696.5

14.1

69

Male

thigh

stori-pleo

CDF

94

18

60.3

72

Male

thigh

stori-pleo

DOD

49

0

0.3

64

Female

buttock

myxoid

DOD

10

2.6

10.3

55

Female

thigh

myxoid

DOD

21

1029.5

23

59

Female

shoulder

stori-pleo

DOD

47

2656

71.1

74

Male

thigh

myxoid

DOD

27

15.6

0.4

59

Female

lower leg

inflammatory

CDF

115

4.6

1.7

46

Male

thigh

stori-pleo

CDF

98

0

0

73

Male

thigh

stori-pleo

CDF

112

0

0

62

Female

forearm

myxoid

CDF

138

145.3

5

59

Female

thigh

stori-pleo

DOD

7

45.3

1.3

49

Male

upper arm

stori-pleo

CDF

87

10.1

0

85

Male

thigh

stori-pleo

CDF

106

0.9

0.2

58

Female

buttock

stori-pleo

DOD

6

103.8

0.1

73

Male

thigh

stori-pleo

CDF

112

145.3

0

78

Male

lower leg

stori-pleo

CDF

119

125.1

0.2

71

Female

lower leg

myxoid

NED

65

31.9

2.4

73

Female

lower leg

myxoid

CDF

25

135.6

7.8

stori-pleo = storiform-pleomorphic type

CDF = continuously disease-free

NED = no evidence of disease

DOD = died of disease

Table 2

Data in 24 patients with liposarcoma

Age (Yrs)

Gender

Site

Histol. Type

Prognosis

Period (mos.)

hTERT

p38

65

Male

thigh

myxoid

NED

93

4

0.4

35

Female

popliteal

myxoid

CDF

108

31.6

1

50

Female

thigh

myxoid

CDF

102

0

0.4

42

Male

shoulder

myxoid

CDF

41

726.6

30.1

65

Male

thigh

myxoid

CDF

56

484.9

38.2

66

Female

thigh

dediff.

CDF

66

271.8

0.2

47

Female

thigh

myxoid

CDF

84

117.5

21.1

58

Male

thigh

myxoid

CDF

76

331.9

0.5

74

Male

thigh

myxoid

DOD

27

148.7

11.2

60

Male

thigh

pleomorphic

CDF

132

145

0.4

51

Male

thigh

pleomorphic

CDF

31

3.1

1.4

66

Male

upper arm

myxoid

CDF

70

29.5

0.7

69

Male

thigh

myxoid

DOD

13

331.2

14

41

Male

lower leg

myxoid

CDF

51

0.8

1.8

47

Male

forearm

dediff.

DOD

12

435.8

2

62

Female

thigh

myxoid

CDF

62

76.5

0.6

68

Male

thigh

myxoid

CDF

100

97.5

1.1

73

Female

buttock

myxoid

DOD

14

391.8

31.6

48

Female

forearm

myxoid

CDF

132

0

1.9

52

Female

thigh

myxoid

CDF

85

91.3

0

48

Male

thigh

myxoid

DOD

15

94.3

0.7

60

Female

thigh

myxoid

CDF

85

58.7

2

36

Male

thigh

myxoid

CDF

81

46.8

0.9

56

Male

thigh

myxoid

CDF

69

191.6

1.2

defiff. = dedifferentiated CDF = continuously disease-free

DOD = died of disease

Table 3

Data in 9 patients with bone MFH

Age (Yrs)

Gender

Site

Histol. Type

Prognosis

Period (mos.)

hTERT

p38

23

Female

femur

stori-pleo

CDF

130

304

0

65

Female

femur

stori-pleo

DOD

37

1405.4

191.1

46

Male

femur

stori-pleo

CDF

141

921.8

36.2

27

Female

clavicle

stori-pleo

CDF

92

323.1

10.3

57

Male

femur

stori-pleo

CDF

93

241.7

0

69

Male

femur

stori-pleo

DOD

8

1278.2

60.3

67

Male

sacrum

stori-pleo

DOD

7

324.5

35.2

38

Male

humerus

stori-pleo

DOD

18

603.6

49.3

57

Female

ilium

stori-pleo

DOD

6

326.5

35

stori-pleo = storiform-pleomorphic type

CDF = continuously disease-free

DOD = died of disease

Quantification of hTERTand p38 MAPK mRNA expression

Total cellular RNA was extracted using a Rneasy Mini Kit (Qiagen, Valencia, CA), and cDNA was synthesized using 1 μg of total RNA using a Transcriptor First Strand cDNA Synthesis Kit (Roche Applied Science, Mannheim, Germany). Quantitative detection of hTERT mRNA and p38 MAPK was performed with the LightCycler TaqMan Master using the LightCycler instrument (Roche Molecular System, Alameda, CA). The primer pairs 5'-CGGAAGAGTGTCTGGAGCAA-3' and 5'-GGATGAAGCGGAGTCTGGA-3' for hTERT, and 5'-ATGCCGAAGATGAACTTTGC-3' and 5'-TCTTATCTGAGTCCAATACAAGCATC-3' for p38 MAPK were used for amplification. PCR used 10 seconds at 95°C, 30 seconds at 60°C and 1 second at 72°C with 45 cycles. Expression of the gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also analyzed in each tumor sample as an indicator of RNA quality. A 3 × 106 of HeLa cell was used as a positive control. Quantification of mRNA expression was indicated by measuring mRNA expression levels of hTERT or p38 MAPK/mRNA levels of the Hela cell ratio.

Statistical analysis

The cumulative prospective of overall survival was calculated using the method of Kaplan-Meier. Statistical significance of the differences between the survival curves was evaluated using the log-rank test. Pearson's product-moment correlation coefficient (r and p values) was used to study the relationship between p38 MAPK and hTERT. Data are presented as the mean ± SD. In all analyses, a p value of < 0.05 was considered to indicate significance.

Results

Overall results of 69 samples

p38 MAPK and hTERT mRNA expression

p38 MAPK expression was demonstrated in 84.1% (58 of 69) and hTERT mRNA expression was demonstrated in 91.3% (63 of 69) of all 69 samples. The levels of p38 MAPK were 13.4 ± 27.7 (range: 0-191.1) and those of hTERT were 336.5 ± 554.8 (range: 0-2656.0) in all samples. We previously reported the data of hTERT in bone and soft tissue MFHs [23, 24].

Correlation between levels of p38 MAPK and hTERT mRNA expression

There was a significant correlation between the values of p38 MAPK expression and hTERT, with increased p38 MAPK expression with higher hTERT in all samples (r = 0.445, p = 0.0001) (Figure 1).
Figure 1

Correlation between p38 and hTERT in all samples. There was a significant correlation between the values of p38 expression and those of hTERT, with increased p38 expression with higher hTERT in all samples (r = 0.445, p = 0.0001).

Prognostic factors

Patients who had a higher than average expression of p38 MAPK had a significantly worse prognosis (5-year survival rate; 38.1%) than other patients overall (73.8%) (p = 0.0036) (Figure 2). There were no significant differences in prognosis between patients who had a higher than average expression of hTERT (5-year survival rate: 38.6%) and those who did not (71.1%) (p = 0.0585).
Figure 2

Kaplan-Meier analysis of the association between the survival and the p38 in all samples. Patients who had a higher than average expression of p38 MAPK had a significantly worse prognosis (5-year survival rate; 38.1%) than other patients (73.8%) overall (p = 0.0036).

Soft tissue MFH samples

p38 MAPK and hTERT mRNA expression

p38 MAPK expression was demonstrated in 77.8% (28 of 36) and hTERT mRNA expression was demonstrated in 88.9% (32 of 36) of soft tissue MFH samples. The levels of p38 MAPK were 9.60 ± 17.5 (range: 0-71.1) and those of hTERT were 371.6 ± 695.9 (range: 0-2656.0).

Correlation between levels of p38 MAPK and hTERT mRNA expression

There was a significant correlation between the values of p38 MAPK expression and hTERT, with increased p38 MAPK expression with higher hTERT in soft tissue MFH samples (r = 0.352, p = 0.0352) (Figure 3).
Figure 3

Correlation between p38 and hTERT in soft tissue MFH samples. There was a significant correlation between the values of p38 expression and those of hTERT (r = 0.352, p = 0.0352).

Prognostic factors

There were no significant differences in prognosis between patients who had a higher than average expression of p38 MAPK (5-year survival rate: 41.7%) and those who did not (65.0%) (p = 0.213). There were no significant differences in prognosis between patients who had a higher than average expression of hTERT (41.7%) and those who did not (62.7%) (p = 0.610).

Liposarcoma samples

p38 MAPK and hTERT mRNA expression

p38 MAPK expression was demonstrated in 95.8% (23 of 24) and hTERT mRNA expression was demonstrated in 91.7% (22 of 24) of LS samples. The levels of p38 MAPK were 6.81 ± 11.5 (range: 0-38.2) and those of hTERT were 171.3 ± 189.9 (range: 0-726.6) in LS samples.

Correlation between levels of p38 MAPK and hTERT mRNA expression

There was a significant correlation between the values of p38 MAPK expression and hTERT, with increased p38 MAPK expression with higher hTERT in LS samples (r = 0.704, p = 0.0001) (Figure 4).
Figure 4

Correlation between p38 and hTERT in liposarcoma samples. There was a significant correlation between the values of p38 expression and those of hTERT (r = 0.704, p = 0.0001).

Prognostic factors

Patients who had a higher than average expression of p38 MAPK (5-year survival rate: 50.0%) had a significantly worse prognosis than other patients (88.9%) (p = 0.0448) in LS patients. There were no significant differences in prognosis between patients who had a higher than average expression of hTERT (62.5%) and those who did not (87.5%) (p = 0.110).

Bone MFH samples

p38 MAPK and hTERT mRNA expression

p38 MAPK expression was demonstrated in 77.8% (7 of 9) and hTERT expression was demonstrated in all (9 of 9) of bone MFH samples. The levels of p38 MAPK were 46.4 ± 58.2 (range: 0-191) and the levels of hTERT were 636.5 ± 453.3 (range: 241.7-1405.4) in bone MFH samples.

Correlation between levels of p38 MAPK and hTERT mRNA expression

There was a significant correlation between the values of p38 MAPK expression and hTERT, with increased p38 MAPK expression with higher hTERT (r = 0.802, p = 0.0093) (Figure 5).
Figure 5

Correlation between p38 and hTERT in bone MFH samples. There was a significant correlation between the values of p38 expression and those of hTERT (r = 0.802, p = 0.0093).

Prognostic factors

Patients who had a higher than average expression of p38 MAPK (5-year survival rate: 0%) had a worse prognosis than other patients (66.7%), but did not reach significant differences (p = 0.202). There were no significant differences in prognosis between patients who had a higher than average expression of hTERT (33.3%) and those who did not (50.0%) (p = 0.904).

Discussion

hTERT is the catalytic telomerase subunit component that copies a template region of its functional RNA subunit to the end of the telomere. In terms of carcinomas, hTERT mRNA expression and telomerase activity are closely associated, and quantification of hTERT mRNA has been reported as an alternative to the measure of telomerase activity [7, 25, 26]. Also, in sarcomas, the correlation between telomerase activity and hTERT has been reported [9, 10, 27]. However, in contrast, previous reports maintained that hTERT expression does not correlate to telomerase activity [12, 23], and hTERT mRNA expression was only studied in the absence of detectable telomerase activity on sarcomas [8, 12, 27, 28]. There is no clear understanding of the discordance between hTERT and telomerase activity in sarcomas [23, 29]. Recently, the presence of telomerase activity and alternative lengthening of telomeres (ALT) in several sarcomas was examined extensively, and these studies indicate a positive correlation between the telomere maintenance mechanism and tumor aggressiveness in several sarcoma types [29]. Furthermore, a positive correlation between hTERT and tumor aggressiveness in several sarcomas has been reported [814]. Therefore, it could be necessary to analyze hTERT, in order to elucidate the telomere maintenance mechanisms and the tumorigenesis of sarcomas.

The predominence of large numbers of protein kinases involved in signal cascades following genotoxic stress is the p38 MAPK [30]. p38 MAPK is shown to induce a wide variety of intracellular responses, with roles in tumorigenesis, cell-cycle regulation, development, inflammation and apoptosis [1517]. Recent studies have suggested that signals transmitted through MAP kinase can regulate hTERT transcription. Epidermal growth factor (EGF) affects the up-regulation of hTERT transcription through the MAP kinase cascades [20]. E26 transformation-specific (Ets) transcription factors, downstream of the mitogen signaling pathways of MAP kinase, regulates hTERT [31]. p38 MAPK may play an important role in the activation of the hTERT promoter by the upstream stimulatory factor (USF) in tumor cells [32]. In the present study, there was a significant positive correlation between the values of p38 MAPK expression and hTERT, with increased p38 MAPK expression with higher hTERT in sarcoma samples. This is the first report to show a correlation between the levels of hTERT mRNA expression and the levels of p38 MAPK in human sarcomas, and these results may suggest that p38 MAPK plays a role in up-regulation of hTERT in soft tissue MFH, liposarcomas, and bone MFH, while we do not have a clear understanding if some factor regulates both p38 MAPK and hTERT expression.

Recent studies have demonstrated that p38 MAPK has diverse roles in the pathogenesis of several cancers and have shown that they are also involved in regulating other functions including the differentiation and proliferation of various cell types [33]. The p38 MAPK pathway is most frequently associated with a tumor suppressor function, based on its negative regulation of proliferation and survival of cells [33, 34]. However, contradictory effects have been observed, a fact that points to the pathway playing a positive role in cell-cycle progression in some carcinoma cells [3537]. In terms of sarcoma cells, inhibition of p38 MAPK activity rescues the antitumor agent fenretinide-mediated cell death in Ewing's sarcoma family of tumors [38], and inhibition of p38 signals results showing a significant reduction in chondrosarcoma cell proliferation mediated by complex effects of p38 signaling on cell-cycle gene expression [39], which suggests that p38 MAPK may play an important role in tumorigenesis in these sarcomas. In the clinical setting, p38 MAPK expression correlates to poor prognosis (p = 0.0036) in overall patients; of high expression of p38 MAPK, indicating the likelihood of a poor outcome and may indicate a positive role of p38 MAPK in tumor proliferation and aggressiveness, in patients with sarcomas. In terms of bone and soft tissue MFH, there were no significant differences in prognosis between patients who had a higher than average expression of p38 MAPK and those who did not. However, patients who had above average p38 (5-year survival rate: soft tissue MFH; 41.7%, bone MFH; 0%) had a worse prognosis than other patients (5-year survival rate: soft tissue MFH; 65.0%, bone MFH; 66.7%), but did not reach significant differences. These results may be due to small numbers of patients. Patients who had a higher than average expression of p38 MAPK (5-year survival rate: 50.0%) had a significantly worse prognosis than other patients (88.9%) (p = 0.0448) in LS patients. Therefore, high expression of p38 MAPK may correlate with a worse prognosis especially for LS patients.

Conclusions

p38 MAPK may be a useful marker in the assessment of hTERT and prognosis. Given that more than 80% of sarcomas express p38 MAPK and hTERT, elucidation of the pathways and target genes of p38 MAPK in sarcomas will yield additional understandings into the pathogenesis of several sarcomas and may lead to novel therapeutic strategies for their treatment.

Notes

Declarations

Authors’ Affiliations

(1)
Department of Orthopaedic Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center
(2)
Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University
(3)
Department of Artificial Joints and Biomaterials, Graduate School of Biomedical Sciences, Hiroshima University

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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