The stem cell‑specific intermediate filament nestin missense variation p.A1199P is associated with pancreatic cancer

  • Authors:
    • Yoko Matsuda
    • Masashi Tanaka
    • Motoji Sawabe
    • Seijiro Mori
    • Masaaki Muramatsu
    • Makiko Naka Mieno
    • Toshiyuki Ishiwata
    • Tomio Arai
  • View Affiliations

  • Published online on: March 4, 2019     https://doi.org/10.3892/ol.2019.10106
  • Pages: 4647-4654
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Abstract

The intermediate filament nestin is upregulated in stem/progenitor cells and cancers, and regulates cell proliferation, migration, invasion and stemness. The present study comparatively analyzed serial autopsies of Japanese patients (n=2,206; males, 1,225; females, 981; median, 80.7 years old; range, 33‑104 years old) with malignant tumors of whole organs, with respect to the clinical information, and 5 single nucleotide polymorphisms of the nestin gene. p.A1199P associated with pancreatic cancer (odds ratio, 4.4; 95% confidence interval, 1.9‑10.0, P=0.001) while it did not associate with malignant neoplasms in other organs. p.A1199P did not associate with precancerous lesions of the pancreas. Single nucleotide polymorphisms of nestin were not associated with sex, drinking, smoking, or body weight. In conclusion, the amino acid 1,199 of nestin is localized in the tail structure of the filament and polymerizes with other intermediate filament proteins. The present results suggest that missense variations of nestin affect pancreatic carcinogenesis in Japanese patients.

Introduction

New cancer cases are rising worldwide because of the growing aging population, and the increasing prevalence of risk factors including smoking, drinking, and obesity. Approximately 14.1 million new cancer cases and 8.2 million deaths occurred worldwide in 2012 (1). In Japan, the most common cause of death was malignant neoplasm (2). A substantial portion of cancer cases and deaths has declined by effective prevention methods, such as tobacco and alcohol control, vaccination, and the use of early detection tests. Inherited genetic mutations play a major role in determining the risk for cancers, and may provide useful information to determine the candidates for early detection tests (3).

Cytoskeletal components regulate cell migration, polarity, and morphology. A neuroepithelial stem cell marker, nestin (NES), is a cytoskeletal protein belonging to the group of class VI intermediate filament (IF) proteins (4,5). NES protein has head, coil, and tail structures. The tail structure of NES is known to interact with other IF proteins, including vimentin, desmin, α-internexin, and synemin, to form heterodimers (6). NES contributes to the disassembly of vimentin during mitosis (7) and to the inactivation of the proapoptotic cyclin-dependent kinase 5 (CDK5) (8). Mouse Cdk5 and Cdc2 induce phosphorylation at both threonine 316 (Thr316) and threonine 1495 (Thr1495) of NES protein (8,9), and phosphorylation of NES modulates mitosis-associated cytoplasmic reorganization during cell mitosis (10).

We have reported that expression of NES in various tumors such as pancreatic cancer (11,12), glioblastoma (13), lung cancer (14), malignant melanoma (15), and uterine cancer (16), regulates cell proliferation, migration, invasion and metastasis. NES regulates stemness in glioblastoma cells through the alteration of cyclin D1 and heat shock cognate 71 kDa protein (13). Phosphorylation of NES at Thr315 and/or Thr1299 regulates cell proliferation (9), and inhibition of both phosphorylation sites suppresses invasion and metastasis of human pancreatic cancer (17).

Data from previous studies (11,12,1821) indicate that inhibition of either NES expression or phosphorylation may be a therapeutic target for several cancers (22). NES is not merely a cytoskeletal protein that serves as a progenitor cell marker, but also is a key regulator of cancer progression processes such as migration, invasion, and metastasis (5,23); therefore, we hypothesized that NES might play important roles in pathogenesis of various cancers. Multiple reports have shown that single nucleotide polymorphisms (SNPs) affect cancer predispositions. However, there have been no reports of a relationship between NES gene variations and cancer. Autopsy is a precious source to analyze various malignant tumors as well as of precursor lesions. In the present study, we comparatively analyzed serially autopsied patients with various malignant neoplasms, based on their clinical information and SNPs.

Patients and methods

Study population

Consecutive autopsy cases (N=2,206) were collected at the Tokyo Metropolitan Geriatric Hospital (Tokyo, Japan) between 1995 and 2012 (24). Participants with family relationships (n=26) were excluded from this study. There were 1,225 men and 981 women with a median age of 80.7 years (range, 33–104 years) and a median body mass index (BMI) of 17.4 kg/m2 (range, 8.1–37.9). The patients were enrolled in the Internet Database of Japanese Single Nucleotide Polymorphisms for Geriatric Research (JG-SNP) (25). We collected information about smoking and drinking from the medical records. The most frequent causes of death were malignancies, infections, and cardiovascular diseases. Approximately 60% of patients had malignant tumors (26). Cancer-bearing subjects include those with any type of cancer, including pathologically verified surgical resected cancer as a past history and occult cancer found on autopsy. We reviewed all the pancreatic specimens from autopsies to determine the presence or absence of pancreatic cancers and pancreatic intraepithelial neoplasia (PanIN). PanIN was defined as microscopic, papillary or flat, non-invasive, epithelial lesions with diameters of 5 mm or less (27). PanIN lesions were classified as PanIN-1A, −1B, −2, or −3 according to previously described criteria (28,29). The present study was approved by the Tokyo Metropolitan Geriatric Hospital Ethics Committee (approval no. 15-02). This study was conducted in accordance with the principles embodied in the Declaration of Helsinki, 2013. Written informed consent was obtained prior to the autopsy from the family members of all participants involved in this study.

Genotyping and genotype calling

Genomic DNA was extracted from the renal cortex using a standard procedure as previously reported (24). All samples were analyzed with Illumina Infinium HumanExome BeadChip Version 1.1 (Illumina, San Diego, CA) by iScan (26). Genotype calling was performed using the Genotyping Module (version 1.9) of the GenomeStudio data analysis software package. Initial genotype clustering was performed using the default Illumina cluster file (HumanExome 12v1-1_A.egt) and the manifest file (HumanExome-12v1-1_A.bmp), using the GenTrain2 clustering algorithm. Validation of the polymorphisms was performed by direct sequencing, using the BigDyeTerminator v3.1 Cycle Sequencing kit on a 3130 Genetic Analyzer (both Applied Biosystems, Foster City, CA, USA) (26). The pathological assessment (YM and TA) and genotyping (MM and MNM) were performed in different institutions in a double-blind fashion to minimize bias. We could not provide the raw data of the present study because we are analyzing our data for use in future studies.

Statistical analysis

We performed Fisher's exact test to determine the association between the phenotypes and SNPs using SPSS version 22 (IBM Corp., Armonk, NY, USA). Power was analyzed using PASS 15.0.5. (NCSS, LLC., Kaysville, UT, USA). P<0.05 was considered to indicate a statistically significant difference. We also analyzed the odds ratio (OR) and 95% confidence interval (CI).

Results

The five SNPs we analyzed in the present study are shown in Table I. They are in exons and located in the tail structure of the NES protein, and four SNPs except for NES p.P1275L are rare variants. All SNPs are miss sense mutations. Two SNPs are possibly damaging. We analyzed the association between SNPs of NES and various cancers in major organs. NES p.A1199P did associate with pancreatic cancer (OR, 4.4; 95% CI, 1.9–10.0, P=0.001 by Fisher's exact test, Table II). Large cell lung carcinoma also showed association to NES p.A1199P (OR, 9.2; 95% CI, 0.9–90.9, P=0.02 by Fisher's exact test, Table II), but few patients harbored this change. The urinary tract malignancies showed an association with NES p.A1199P (P=0.053). Malignant neoplasms in other organs such as lung, colon, stomach, brain, and blood cancers did not associate with NES p.A1199P (Fisher's exact test, Tables II and III).

Table I.

Single nucleotide polymorphisms of nestin.

Table I.

Single nucleotide polymorphisms of nestin.

NumberAllelesIn-exonMutation(s)rs numberPredictionMinor allele frequency
exm109872[A/G]EXON Missense_P1275Lrs3748570Benign0.2413
exm109911[T/C]EXON Missense_S1016Nrs2365718Possibly damaging0.0043
exm109937[T/G]EXONMissense_L791Irs77202633Benign0.0553
exm1719129[G/C]EXON Missense_A1199Prs78303930Possibly damaging0.0170
exm1719137[A/G]EXONMissense_V876Ars143673331Benign0.0028

Table II.

Malignant tumors in major organs and NES p.A1199P.

Table II.

Malignant tumors in major organs and NES p.A1199P.

OrganTypeTumor + (%)Tumor - (%)OR95% CIP-value
LungCC253 (11.5)1,871 (85.0)
GC+GG7 (0.3)71 (3.2)0.7290.332–1.6030.430
Large cell carcinoma/lungCC3 (0.1)2,121 (96.3)
GC+GG1 (0)77 (3.5)9.1740.944–90.09090.020a
StomachCC239 (10.8)1,887 (85.6)
GC+GG7 (0.3)72 (3.3)0.7670.349–1.6860.509
ColorectumCC209 (9.5)1,917 (86.9)
GC+GG4 (0.2)75 (3.4)0.4890.177–1.3510.159
PancreasCC47 (2.1)2,078 (94.3)
GC+GG7 (0.3)71 (3.2)4.3671.905–100.001b
LiverCC68 (3.1)2,058 (93.3)
GC+GG0 (0)79 (3.6)N.D.N.D.0.106
Biliary tractCC61 (2.8)2,065 (93.7)
GC+GG2 (0.1)77 (3.5)0.8800.211–4.2190.860
KidneyCC32 (1.5)2,094 (95.0)
GC+GG  1 (0)78 (3.5)0.8390.113–6.2110.863
Urinary tractCC41 (1.9)2,085 (94.6)
GC+GG4 (0.2)75 (3.4)2.7100.947–7.7520.053
ProstateCC197 (16.0)987 (80.4)
GC+GG7 (0.6)37 (3.0)0.9480.416–2.1550.898
BloodCC195 (8.9)1,930 (87.6)
GC+GG4 (0.2)74 (3.4)0.5350.194–1.4790.221
BrainCC2 (0.1)2,122 (96.4)
GC+GG0 (0)78 (3.5)N.D.N.D.0.786

a P<0.05

b P<0.001. OR, odds ratio of GC+GG to CC; CI, confidence interval; N.D., not determined.

Table III.

Other malignant tumors and NES p.A1199P.

Table III.

Other malignant tumors and NES p.A1199P.

OrganTypeTumor + (%)Tumor - (%)OR95% CIP-value
Adenocarcinoma/lungCC115 (5.2)2,009 (91.2)
GC+GG2 (0.1)76 (3.5)0.4600.112–1.8940.270
Squamous cell carcinoma/lungCC77 (3.5)2,047 (93.0)
GC+GG3 (0.1)75 (3.4)1.0640.328–4.7850.918
Adenosquamous carcinoma lungCC8 (0.4)2,116 (96.1)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.587
Small cell carcinoma lungCC55 (2.5)2,069 (94.0)
GC+GG2 (0.1)76 (3.5)0.9900.237–4.1320.989
Unclassified cancer lungCC11 (0.5)2,113 (96.0)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.524
MesotheliomaCC1 (0.0)2,124 (96.4)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.848
Esophageal cancerCC32 (1.5)2,091 (95.0)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.275
Colon cancerCC163 (7.4)1,963 (89.0)
GC+GG3 (0.1)76 (3.4)0.4750.148–1.5240.201
Rectal cancerCC52 (2.4)2,074 (94.1)
GC+GG1 (0.0)78 (3.5)0.5110.070–3.7450.501
Small intestine cancerCC11 (0.5)2,115 (95.9)
GC+GG0 (0.0)79 (3.6)N.D.N.D.0.522
Lymphocytic leukemiaCC18 (0.8)2,107 (95.6)
GC+GG1 (0.0)77 (3.5)1.5200.200–11.4940.683
Malignant lymphomaCC119 (5.4)2,005 (91.1)
GC+GG1 (0.0)77 (3.5)N.D.N.D.0.099
Myelodysplastic syndromeCC39 (1.8)2,086 (94.7)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.227
Myelogenous leukemiaCC104 (4.7)2,021 (91.7)
GC+GG2 (0.1)76 (3.4)0.5120.124–2.1100.345
MyelomaCC38 (1.7)2,087 (94.7)
GC+GG1 (0.0)77 (3.5)0.7130.097–5.2630.739
Breast cancerCC74 (3.4)2,050 (93.1)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.094
Uterine cancerCC20 (2.1)919 (94.4)
GC+GG0 (0.0)35 (3.6)N.D.N.D.0.383
Ovarian cancerCC5 (0.5)939 (95.9)
GC+GG0 (0.0)35 (3.6)N.D.N.D.0.666
Thyroid cancerCC52 (2.4)2,072 (94.1)
GC+GG2 (0.1)76 (3.5)1.0480.250–4.3860.948
SarcomaCC7 (0.3)2,117 (96.1)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.612
MelanomaCC1 (0.0)2,123 (96.4)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.848
Skin cancerCC9 (0.4)2,112 (96.0)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.564
Head and neck cancerCC25 (1.1)2,099 (95.3)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.335
Other tumorCC9 (0.4)2,115 (99.2)
GC+GG0 (0.0)9 (0.4)N.D.N.D.0.565
Unclassified tumorCC4 (0.2)2,120 (96.3)
GC+GG0 (0.0)78 (3.5)N.D.N.D.0.701

[i] OR, odds ratio of GC+GG to CC; CI, confidence interval; N.D., not determined.

Other SNPs except for NES p.A1199P did not associate with pancreatic cancer (Table IV); therefore, we performed further analysis about NES p.A1199P. Alleles of NES p.A1199P were CC (n=2,127), GC (n=78) and GG (n=1); GC and GG alleles showed that amino acid number 1199 was changed from alanine to proline. It did not associate with sex, drinking, smoking, or BMI (Table V).

Table IV.

SNPs of nestin and pancreatic cancer.

Table IV.

SNPs of nestin and pancreatic cancer.

SNPReference no.OR95% CIP-value
P1275Lrs37485700.6300.366–1.0850.116
S1016Nrs23657181.0470.058–18.7901.000
L791Irs772026330.7380.289–1.8850.670
A1199Prs783039304.3671.905–100.001a
V876Ars1436733311.9510.100–38.1741.000

a P<0.001. CI, confidence interval; SNP, single nucleotide polymorphism; OR, odds ratio.

Table V.

Patients and NES p.A1199P.

Table V.

Patients and NES p.A1199P.

ComparisonCCGC+GGOR95% CIP-value
Sex (%)
  Male1,182 (53.6)43 (1.9)
  Female945 (42.8)36 (1.6)0.9550.608–1.4990.841
Drinking habit (%)
  Drinker674 (34.0)27 (1.4)
  Non-drinker1,240 (62.6)41 (2.1)1.2120.739–1.9880.447
Smoking habit (%)
  Smoker1,023 (50.4)38 (1.9)
  Non-smoker936 (46.1)33 (1.6)1.0540.655–1.6950.829
BMI (%)
  BMI ≥25948 (43.4)36 (1.6)
  BMI <251,159 (53.0)43 (2.0)1.0240.652–1.6080.919

[i] OR, odds ratio of GC+GG to CC; NES, nestin; CI, confidence interval; BMI, body mass index.

We examined the association of NES p.A1199P with precancerous lesions, PanINs (Table VI). PanIN-1A, −1B, −2 and −3 did not associate with NES p.A1199P. In addition, there were no significance between NES p.A1199P and low grade PanIN (PpanIN-1 and −2), or PanIN and cancer. Presence of PanIN-3 and pancreatic cancer was associated with NES.p.A1199P (P=0.007, Table VI). All pancreatic cancers were invasive ductal adenocarcinomas. Pancreatic cancer cases with GC+GG of NES p.A1199P showed a tendency to be well differentiated as compared to CC (P=0.085, data not shown). Sex, age, and tumor stage had no association with NES p.A1199P.

Table VI.

Pancreatic intraepithelial neoplasia and NES p.A1199P.

Table VI.

Pancreatic intraepithelial neoplasia and NES p.A1199P.

VariableType+ (%)− (%)OR95% CIP-value
PanIN-1ACC1,137 (51.6)990 (44.9)
GC+GG42 (1.9)36 (1.6)1.0160.646–1.5970.646
PanIN-1BCC911 (41.3)1,216 (55.1)
GC+GG31 (1.4)47 (2.1)0.8800.555–1.3970.595
PanIN-2CC255 (11.6)1,870 (84.9)
GC+GG7 (0.3)71 (3.2)0.7230.329–1.5900.673
PanIN-3CC29 (1.3)2,096 (95.1)
GC+GG2 (0.1)76 (3.4)1.9010.446–8.1300.672
Low grade PanINCC1,174 (53.2)953 (43.2)
GC+GG43 (2.0)35 (1.6)0.9970.633–1.5700.666
PanIN and cancerCC1,189 (53.9)938 (42.5)
GC+GG44 (2.0)34 (1.5)1.0200.647–1.6100.672
PanIN-3 and cancerCC72 (3.3)2,054 (93.2)
GC+GG8 (0.4)70 (3.2)3.2151.493–6.9440.007a

a P<0.01. Cancer indicates pancreatic invasive ductal carcinoma. Low grade PanIN includes PanIN-1 and −2. NES, nestin; PanIN, pancreatic intraepithelial neoplasia; OR, odds ratio of GC+GG to CC; CI, confidence interval.

Discussion

In the present study, we investigated the relationship between SNPs of NES and malignant neoplasm predispositions in autopsied Japanese patients. Our data suggests that NES p.A1199P associates with the occurrence of pancreatic cancer, though other malignant neoplasms did not show any association to SNPs of NES. Furthermore, NES p.A1199P did not associate with occurrence of PanIN, suggesting that only a small portion of PanINs are precancerous lesions (24). The high incidence rate of PanINs and our previous study (24) both support this conclusion.

Morbidity and mortality of pancreatic cancers have been increasing worldwide (30,31). In Japan, pancreatic cancer is the fifth and fourth leading cause of cancer-related death in men and women, respectively (32). Risk factors for pancreatic cancer are tobacco use (33), heavy alcohol consumption, diabetes, obesity, pancreatitis, low 25-(OH) vitamin D levels, and aging (34,35). The vast majority of pancreatic cancers are thought to arise from PanINs; high-grade PanINs (carcinomas in situ) are considered as precursors of pancreatic cancer (29,3638). Approximately 5–10% of patients with pancreatic cancer have family histories of pancreatic cancer (39,40). Recent studies for pancreatic ductal adenocarcinoma (PDAC) using Caucasian populations have identified associations with chromosome bands of ABO, KLF5, NR5A2, CLPTM1L-TERT (41,42); LINC-PINT, BRCAR1, PDX1, ZNRF3, PVT1 (43); LINC00673, SUGCT and TP63 (44). A recent study also showed that three SNPs in NR5A2, MYC and CLPTM1L-TERT represent independent risk factors of pancreatic cancer; NR5A2 expression in the pancreatic cancers was markedly decreased (45). In Japanese populations, SNPs of NR5A2 have shown a significant association with PDAC (46,47). Previously, we have reported that six SNPs (rs7016880, rs10096633, rs10503669, rs12678919, rs17482753, and rs328) that associated with blood lipid levels were associated with the risk for pancreatic cancer in the same cohort (24).

In the present study, we focused on SNPs of NES in autopsied patients, because NES plays important roles in many processes in various organ neoplasms as well as tissue regeneration. A previous report has shown that SNPs of NES (rs11582300 and rs3748570) were associated with early-onset coronary heart diseases in Irish people (48). The present study is the first report to clarify the relationship between SNPs of NES and various malignancies. Amino acid 1199 of NES is conserved in various mammals including primates and pigs, and is located in the tail lesion of NES (Fig. 1). The tail lesion polymerizes with other IF proteins, and regulates cell morphology, migration, and mitosis. In the present study, we did not find any association between clinicopathological characteristics of pancreatic cancer patients and NES p.A1199P. Pancreatic exocrine progenitor cells of mice express NES protein (49), and pancreatic cancer might originate from pancreatic exocrine progenitor cells. These data suggest that NES p.A1199P might influence carcinogenesis steps in the pancreas. We need biological studies and a larger cohort study to clarify molecular mechanisms of NES p.A1199P.

The present study has several limitations. The average age of our patients is much higher than that observed in most patients with pancreatic cancer as previously reported (24). Japan is experiencing a ‘super-aging’ society. PDAC is projected to surpass breast, prostate, and colorectal cancers to become the second leading cause of cancer-related deaths by 2030 in the U.S (50). In this context, it is definitely important to identify the characteristics of age-related pancreatic carcinogenesis. Furthermore, the power of statistical analysis in the present study was 48.6% between presence of pancreatic cancer and NES p.A1199P. We need further analysis using large scale different cohort.

In conclusion, we found that missense variations of NES appear to affect pancreatic carcinogenesis in Japanese patients by an undetermined mechanism.

Acknowledgements

Not applicable.

Funding

The present study was supported, in part, by a grant from the Smoking Research Foundation and a grant-in-aid from the Japan Society for the Promotion of Science (C; grant no. 16KT0125). The present study was also supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, GMEXT/JSPS KAKENHI Grants (grant nos. A-16H01872, A-25242062, A-22240072, B-21390459, C-26670481, C-21590411 and CER-24650414), Grants-in-Aid for Research on Intractable Diseases (Mitochondrial Disorders) from the Ministry of Health, Labor, and Welfare of Japan (grant nos. 23-016, 23–116 and 24-005), the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, AMED (grant nos. 15ek0109088h0001 and 15ek0109088s0401), the Takeda Science Foundation, and the Joint Usage/Research Program of the Medical Research Institute, Tokyo Medical and Dental University.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

YM, MT and TA conceived and directed the project, analyzed the data and wrote the manuscript. MS, SM, MM, MNM and TI analyzed data and supervised. All authors have read and approved the manuscript.

Ethics approval and consent to participate

The present study was approved by the Tokyo Metropolitan Geriatric Hospital Ethics Committee (approval no. 15-02). This study was conducted in accordance with the principles embodied in the Declaration of Helsinki, 2013. Written informed consent was obtained prior to the autopsy from the family members of all participants involved in this study.

Patient consent for publication

Written informed consent was obtained prior to the autopsy from the family members of all participants involved in this study.

Competing interests

The authors declare that they have no competing interests.

References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Hirata M, Nagai A, Kamatani Y, Ninomiya T, Tamakoshi A, Yamagata Z, Kubo M, Muto K, Kiyohara Y, Mushiroda T, et al: Overview of BioBank Japan follow-up data in 32 diseases. J Epidemiol. 27 (3 Suppl):S22–S28. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Srinivasan S, Clements JA and Batra J: Single nucleotide polymorphisms in clinics: Fantasy or reality for cancer? Crit Rev Clin Lab Sci. 53:29–39. 2016. View Article : Google Scholar : PubMed/NCBI

4 

Lendahl U, Zimmerman LB and McKay RD: CNS stem cells express a new class of intermediate filament protein. Cell. 60:585–595. 1990. View Article : Google Scholar : PubMed/NCBI

5 

Ishiwata T, Matsuda Y and Naito Z: Nestin in gastrointestinal and other cancers: Effects on cells and tumor angiogenesis. World J Gastroenterol. 17:409–418. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Sjöberg G, Jiang WQ, Ringertz NR, Lendahl U and Sejersen T: Colocalization of nestin and vimentin/desmin in skeletal muscle cells demonstrated by three-dimensional fluorescence digital imaging microscopy. Exp Cell Res. 214:447–458. 1994. View Article : Google Scholar : PubMed/NCBI

7 

Chou YH, Khuon S, Herrmann H and Goldman RD: Nestin promotes the phosphorylation-dependent disassembly of vimentin intermediate filaments during mitosis. Mol Biol Cell. 14:1468–1478. 2003. View Article : Google Scholar : PubMed/NCBI

8 

Sahlgren CM, Mikhailov A, Vaittinen S, Pallari HM, Kalimo H, Pant HC and Eriksson JE: Cdk5 regulates the organization of Nestin and its association with p35. Mol Cell Biol. 23:5090–5106. 2003. View Article : Google Scholar : PubMed/NCBI

9 

Matsuda Y, Suzuki G, Kusano T, Kawamoto Y, Yoshimura H, Fuse A, Yokota H, Naito Z and Ishiwata T: Phosphorylation of Thr(1495) of nestin in a mouse model of cerebral ischemia and reperfusion damage. Pathol Int. 63:448–456. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Sahlgren CM, Mikhailov A, Hellman J, Chou YH, Lendahl U, Goldman RD and Eriksson JE: Mitotic reorganization of the intermediate filament protein nestin involves phosphorylation by cdc2 kinase. J Biol Chem. 276:16456–16463. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Matsuda Y, Yoshimura H, Ueda J, Naito Z, Korc M and Ishiwata T: Nestin delineates pancreatic cancer stem cells in metastatic foci of NOD/Shi-scid IL2Rγ(null) (NOG) mice. Am J Pathol. 184:674–685. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Matsuda Y, Naito Z, Kawahara K, Nakazawa N, Korc M and Ishiwata T: Nestin is a novel target for suppressing pancreatic cancer cell migration, invasion and metastasis. Cancer Biol Ther. 11:512–523. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Matsuda Y, Ishiwata T, Yoshimura H, Hagio M and Arai T: Inhibition of nestin suppresses stem cell phenotype of glioblastomas through the alteration of post-translational modification of heat shock protein HSPA8/HSC71. Cancer Lett. 357:602–611. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Narita K, Matsuda Y, Seike M, Naito Z, Gemma A and Ishiwata T: Nestin regulates proliferation, migration, invasion and stemness of lung adenocarcinoma. Int J Oncol. 44:1118–1130. 2014. View Article : Google Scholar : PubMed/NCBI

15 

Akiyama M, Matsuda Y, Ishiwata T, Naito Z and Kawana S: Inhibition of the stem cell marker nestin reduces tumor growth and invasion of malignant melanoma. J Invest Dermatol. 133:1384–1387. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Sato A, Ishiwata T, Matsuda Y, Yamamoto T, Asakura H, Takeshita T and Naito Z: Expression and role of nestin in human cervical intraepithelial neoplasia and cervical cancer. Int J Oncol. 41:441–448. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Matsuda Y, Ishiwata T, Yoshimura H, Yamahatsu K, Minamoto T and Arai T: Nestin phosphorylation at threonines 315 and 1299 correlates with proliferation and metastasis of human pancreatic cancer. Cancer Sci. 108:354–361. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Kawamoto M, Ishiwata T, Cho K, Uchida E, Korc M, Naito Z and Tajiri T: Nestin expression correlates with nerve and retroperitoneal tissue invasion in pancreatic cancer. Hum Pathol. 40:189–198. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Matsuda Y, Kure S and Ishiwata T: Nestin and other putative cancer stem cell markers in pancreatic cancer. Med Mol Morphol. 45:59–65. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Yamahatsu K, Matsuda Y, Ishiwata T, Uchida E and Naito Z: Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis. Int J Oncol. 40:1345–1357. 2012.PubMed/NCBI

21 

Liu C, Chen B, Zhu J, Zhang R, Yao F, Jin F, Xu H and Lu P: Clinical implications for nestin protein expression in breast cancer. Cancer Sci. 101:815–819. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Matsuda Y, Ishiwata T, Yoshimura H, Yamashita S, Ushijima T and Arai T: Systemic administration of small interfering RNA targeting human nestin inhibits pancreatic cancer cell proliferation and metastasis. Pancreas. 45:93–100. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Neradil J and Veselska R: Nestin as a marker of cancer stem cells. Cancer Sci. 106:803–811. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Matsuda Y, Tanaka M, Sawabe M, Mori S, Muramatsu M, Mieno MN, Furukawa T and Arai T: Relationship between pancreatic intraepithelial neoplasias, pancreatic ductal adenocarcinomas, and single nucleotide polymorphisms in autopsied elderly patients. Genes Chromosomes Cancer. 57:12–18. 2018. View Article : Google Scholar : PubMed/NCBI

25 

Sawabe M, Arai T, Kasahara I, Esaki Y, Nakahara K, Hosoi T, Orimo H, Takubo K, Murayama S, Tanaka N, et al: Developments of geriatric autopsy database and Internet-based database of Japanese single nucleotide polymorphisms for geriatric research (JG-SNP). Mech Ageing Dev. 125:547–552. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Yamada M, Sato N, Ikeda S, Arai T, Sawabe M, Mori S, Yamada Y, Muramatsu M and Tanaka M: Association of the chromodomain helicase DNA-binding protein 4 (CHD4) missense variation p.D140E with cancer: Potential interaction with smoking. Genes Chromosomes Cancer. 54:122–128. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Longnecker DS, Adsay NV, Fernandez-del Castillo C, Hruban RH, Kasugai T, Klimstra DS, Klöppel G, Lüttges J, Memoli VA, Tosteson TD, et al: Histopathological diagnosis of pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms: Interobserver agreement. Pancreas. 31:344–349. 2005. View Article : Google Scholar : PubMed/NCBI

28 

Hruban RH, Boffetta P, Hiraoka N, Iacobuzio-Donahue C, Kato Y, Kern SE, Kloppel G, Marita A, Offerhaus GJA and Pitman MB: Tumours of the pancreas. Bosman F.T, Carneiro F, Hruban R.H and Theise N.D: WHO classification of tumours of the digestive system. IARC; Lyon: 2010

29 

Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra DS, Klöppel G, Longnecker DS, et al: Pancreatic intraepithelial neoplasia: A new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 25:579–586. 2001. View Article : Google Scholar : PubMed/NCBI

30 

Warshaw AL and Fernández-del Castillo C: Pancreatic carcinoma. N Engl J Med. 326:455–465. 1992. View Article : Google Scholar : PubMed/NCBI

31 

Bidoli E, Fratino L, Bruzzone S, Pappagallo M, De Paoli P, Tirelli U and Serraino D: Time trends of cancer mortality among elderly in Italy, 1970–2008: An observational study. BMC Cancer. 12:4432012. View Article : Google Scholar : PubMed/NCBI

32 

Japan TEBotCSi: Cancer statics in Japan 2017. Found Pro Cancer Res. 2018.

33 

MacLeod SL and Chowdhury P: The genetics of nicotine dependence: Relationship to pancreatic cancer. World J Gastroenterol. 12:7433–7439. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Pandol S, Gukovskaya A, Edderkaoui M, Dawson D, Eibl G and Lugea A: Epidemiology, risk factors, and the promotion of pancreatic cancer: Role of the stellate cell. J Gastroenterol Hepatol. 27 Suppl 2:S127–S134. 2012. View Article : Google Scholar

35 

Matsuda Y, Ishiwata T, Yachida S, Suzuki A, Hamashima Y, Hamayasu H, Yoshimura H, Honma N, Aida J, Takubo K and Arai T: Clinicopathological features of 15 occult and 178 clinical pancreatic ductal adenocarcinomas in 8339 autopsied elderly patients. Pancreas. 45:234–240. 2016. View Article : Google Scholar : PubMed/NCBI

36 

Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, Hruban RH, Maitra A, Kinzler K, Vogelstein B and Goggins M: Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology. 142:730–733.e9. 2012. View Article : Google Scholar : PubMed/NCBI

37 

Mukada T and Yamada S: Dysplasia and carcinoma in situ of the exocrine pancreas. Tohoku J Exp Med. 137:115–124. 1982. View Article : Google Scholar : PubMed/NCBI

38 

Basturk O, Hong SM, Wood LD, Adsay NV, Albores-Saavedra J, Biankin AV, Brosens LA, Fukushima N, Goggins M, Hruban RH, et al: A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am J Surg Pathol. 39:1730–1741. 2015. View Article : Google Scholar : PubMed/NCBI

39 

Hruban RH, Canto MI, Goggins M, Schulick R and Klein AP: Update on familial pancreatic cancer. Adv Surg. 44:293–311. 2010. View Article : Google Scholar : PubMed/NCBI

40 

Klein AP: Genetic susceptibility to pancreatic cancer. Mol Carcinog. 51:14–24. 2012. View Article : Google Scholar : PubMed/NCBI

41 

Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, Fuchs CS, Petersen GM, Arslan AA, Bueno-de-Mesquita HB, Gross M, Helzlsouer K, Jacobs EJ, et al: Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 41:986–990. 2009. View Article : Google Scholar : PubMed/NCBI

42 

Petersen GM, Amundadottir L, Fuchs CS, Kraft P, Stolzenberg-Solomon RZ, Jacobs KB, Arslan AA, Bueno-de-Mesquita HB, Gallinger S, Gross M, et al: A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 42:224–228. 2010. View Article : Google Scholar : PubMed/NCBI

43 

Wolpin BM, Rizzato C, Kraft P, Kooperberg C, Petersen GM, Wang Z, Arslan AA, Beane-Freeman L, Bracci PM, Buring J, et al: Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet. 46:994–1000. 2014. View Article : Google Scholar : PubMed/NCBI

44 

Childs EJ, Mocci E, Campa D, Bracci PM, Gallinger S, Goggins M, Li D, Neale RE, Olson SH, Scelo G, et al: Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. Nat Genet. 47:911–916. 2015. View Article : Google Scholar : PubMed/NCBI

45 

Zhang M, Wang Z, Obazee O, Jia J, Childs EJ, Hoskins J, Figlioli G, Mocci E, Collins I, Chung CC, et al: Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. Oncotarget. 7:66328–66343. 2016.PubMed/NCBI

46 

Low SK, Kuchiba A, Zembutsu H, Saito A, Takahashi A, Kubo M, Daigo Y, Kamatani N, Chiku S, Totsuka H, et al: Genome-wide association study of pancreatic cancer in Japanese population. PLoS One. 5:e118242010. View Article : Google Scholar : PubMed/NCBI

47 

Ueno M, Ohkawa S, Morimoto M, Ishii H, Matsuyama M, Kuruma S, Egawa N, Nakao H, Mori M, Matsuo K, et al: Genome-wide association study-identified SNPs (rs3790844, rs3790843) in the NR5A2 gene and risk of pancreatic cancer in Japanese. Sci Rep. 5:170182015. View Article : Google Scholar : PubMed/NCBI

48 

Meng W, Patterson CC, Belton C, Hughes A and McKeown PP: Variants in the nestin gene and coronary heart disease. Circ J. 72:1538–1539. 2008. View Article : Google Scholar : PubMed/NCBI

49 

Rovira M, Scott SG, Liss AS, Jensen J, Thayer SP and Leach SD: Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci USA. 107:75–80. 2010. View Article : Google Scholar : PubMed/NCBI

50 

Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM and Matrisian LM: Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74:2913–2921. 2014. View Article : Google Scholar : PubMed/NCBI

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May 2019
Volume 17 Issue 5

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Online ISSN:1792-1082

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Copy and paste a formatted citation
APA
Matsuda, Y., Tanaka, M., Sawabe, M., Mori, S., Muramatsu, M., Naka Mieno, M. . ... Arai, T. (2019). The stem cell‑specific intermediate filament nestin missense variation p.A1199P is associated with pancreatic cancer. Oncology Letters, 17, 4647-4654. https://doi.org/10.3892/ol.2019.10106
MLA
Matsuda, Y., Tanaka, M., Sawabe, M., Mori, S., Muramatsu, M., Naka Mieno, M. ., Ishiwata, T., Arai, T."The stem cell‑specific intermediate filament nestin missense variation p.A1199P is associated with pancreatic cancer". Oncology Letters 17.5 (2019): 4647-4654.
Chicago
Matsuda, Y., Tanaka, M., Sawabe, M., Mori, S., Muramatsu, M., Naka Mieno, M. ., Ishiwata, T., Arai, T."The stem cell‑specific intermediate filament nestin missense variation p.A1199P is associated with pancreatic cancer". Oncology Letters 17, no. 5 (2019): 4647-4654. https://doi.org/10.3892/ol.2019.10106