The Role of Claudin-1 in Enhancing Pancreatic Cancer Aggressiveness and Drug Resistance via Metabolic Pathway Modulation
Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Antibodies
2.2. Immunohistochemical Analysis of Surgical Specimens and Immunocytochemistry of Cell Blocks
2.3. Cell Culture and Treatment
2.4. Western Blotting
2.5. Cell Proliferation and Plate Colony Formation Assay
2.6. Wound-Healing, Migration, and Invasion Assays
2.7. Proteome Analysis
2.8. Immunocytochemistry
2.9. Cellular Fractionation and Co-Immunoprecipitation Assays
2.10. RNA Interference
2.11. Apoptosis Assay
2.12. Statistical Analysis
2.13. Ethics Statement and Patient Consent
3. Results
3.1. Expression Profiles of Cldn1 in Surgical Specimens of PDAC, PanIN, and Normal Ducts
3.2. Cldn1 Contributes to the Proliferation, Migration, and Invasion of Pancreatic Cancer Cells
3.3. Comprehensive Proteome Analysis Showed AKRs as Candidates That Interact with Cldn1 in Pancreatic Cancer Cells
3.4. Cldn1 KO and AKR Superfamily Knockdown Attenuate Drug Resistance
3.5. Knockdown of the AKR Superfamily Also Attenuates the Proliferation and Invasion Abilities of PK45H Cells
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
PDAC | pancreatic ductal adenocarcinoma |
Cldn1 | claudin-1 |
AKR | aldo-keto reductase |
EMT | epithelial-mesenchymal transition |
DD | dihydrodiol dehydrogenase |
H-score | histological score |
GO | Gene Ontology |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
DAPI | 4,6-diamidino-2-phenylindole |
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Univariate Analysis | Multivariate Analysis | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Variables | Hazard Ratio | 95%CI (Lower) | 95%CI (Upper) | p-Value | Hazard Ratio | 95%CI (Lower) | 95%CI (Upper) | p-Value | ||
Cldn1 positive | 2.03 | 1.06 | 3.91 | 0.033 | * | 2.21 | 1.13 | 4.32 | 0.021 | * |
Male | 0.74 | 0.42 | 1.29 | 0.284 | ||||||
Age > 65 | 1.04 | 0.58 | 1.88 | 0.890 | ||||||
ASA: 3 | 1.21 | 0.48 | 3.06 | 0.684 | ||||||
BMI > 25 | 1.09 | 0.54 | 2.18 | 0.816 | ||||||
Tumor location: Head | 1.17 | 0.64 | 2.12 | 0.616 | ||||||
Resectability: BR/UR | 1.44 | 0.82 | 2.55 | 0.208 | ||||||
Neoadjuvant treatment | 1.14 | 0.63 | 2.06 | 0.655 | ||||||
Poorly differentiated carcinoma | 1.21 | 0.51 | 2.84 | 0.669 | ||||||
Lymphatic invasion | 1.38 | 0.77 | 2.48 | 0.275 | ||||||
Vascular invasion | 1.18 | 0.66 | 2.11 | 0.585 | ||||||
Neural invasion | 0.93 | 0.46 | 1.87 | 0.843 | ||||||
Pleural invasion | 0.98 | 0.50 | 1.92 | 0.955 | ||||||
Portal vein invasion | 0.90 | 0.45 | 1.80 | 0.761 | ||||||
T-stage: pT3-4 | 1.74 | 0.89 | 3.40 | 0.108 | ||||||
N-stage: pN1 | 1.98 | 1.08 | 3.63 | 0.027 | * | |||||
TNM stage: pStage III/IV | 2.89 | 1.59 | 5.27 | <0.001 | ** | 2.85 | 1.50 | 5.42 | 0.001 | ** |
High pre-operative CA19-9 (>37 U/mL) | 1.35 | 0.76 | 2.43 | 0.308 | ||||||
High post-operative CA19-9 (>37 U/mL) | 3.66 | 1.96 | 6.85 | <0.001 | ** | 3.32 | 1.73 | 6.36 | <0.001 | ** |
Accession | Protein Names | Gene Names | Ratio (KO-1/wt) | p Value (KO-1vs wt) | Ratio (KO-2/wt) | p Value (KO-2vs wt) |
---|---|---|---|---|---|---|
P47985 | Cytochrome b-c1 complex subunit Rieske, mitochondrial | UQCRFS1 | 0.001 | 3.8 × 10−5 | 0.001 | 3.8 × 10−5 |
Q14697-2 | Isoform 2 of Neutral alpha-glucosidase AB | GANAB | 0.003 | 8.5 × 10−6 | 0.44 | 7.1 × 10−3 |
P52895 | Aldo-keto reductase family 1 member C2 | AKR1C2 | 0.06 | 2.4 × 10−6 | 0.01 | 8.7 × 10−7 |
P40261 | Nicotinamide N-methyltransferase | NNMT | 0.09 | 9.2 × 10−11 | 0.15 | 7.0 × 10−11 |
O00469-1 | procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 | PLOD2 | 0.21 | 3.1 × 10−3 | 0.31 | 6.0 × 10−3 |
P42330 | Aldo-keto reductase family 1 member C3 | AKR1C3 | 0.37 | 1.4 × 10−7 | 0.19 | 9.2 × 10−10 |
P45954 | Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial | ACADSB | 0.37 | 2.0 × 10−2 | 0.40 | 4.7 × 10−2 |
O75828 | Carbonyl reductase [NADPH] 3 | CBR3 | 0.40 | 7.4 × 10−7 | 0.39 | 1.5 × 10−8 |
Q02127 | Dihydroorotate dehydrogenase (Quinone), mitochondrial | DHODH | 0.46 | 3.0 × 10−2 | 0.31 | 2.6 × 10−3 |
P48163 | NADP-dependent malic enzyme | ME1 | 0.49 | 2.6 × 10−5 | 0.34 | 4.1 × 10−5 |
P08243-1 | Asparagine synthetase [glutamine-hydrolyzing] | ASNS | 0.50 | 2.5 × 10−8 | 0.54 | 1.6 × 10−7 |
O14521 | Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial | SDHD | 0.51 | 2.3 × 10−4 | 0.47 | 8.2 × 10−5 |
Q15125 | 3-beta-hydroxysteroid-Delta(8), Delta(7)-isomerase | EBP | 0.54 | 9.6 × 10−5 | 0.60 | 5.7 × 10−4 |
Q01581 | Hydroxymethylglutaryl-CoA synthase, cytoplasmic | HMGCS1 | 0.55 | 5.7 × 10−6 | 0.45 | 1.7 × 10−3 |
P15121 | Aldose reductase | AKR1B1 | 0.56 | 1.2 × 10−8 | 0.31 | 3.0 × 10−7 |
Q9BWD1 | Acetyl-CoA acetyltransferase, cytosolic | ACAT2 | 0.58 | 6.1 × 10−4 | 0.66 | 8.2 × 10−4 |
P52788-1 | Spermine synthase | SMS | 0.58 | 1.3 × 10−4 | 0.43 | 5.3 × 10−7 |
P30566 | Adenylosuccinate lyase | ADSL | 0.59 | 6.8 × 10−6 | 0.31 | 5.3 × 10−8 |
P09601 | Heme oxygenase 1 | HMOX1 | 0.59 | 6.5 × 10−3 | 0.13 | 1.7 × 10−4 |
P04181-1 | Ornithine aminotransferase, mitochondrial | OAT | 0.60 | 3.0 × 10−4 | 0.64 | 4.4 × 10−4 |
P15531 | Nucleoside diphosphate kinase A | NME1 | 0.60 | 5.7 × 10−4 | 0.50 | 6.4 × 10−4 |
O00330-1 | Pyruvate dehydrogenase protein X component, mitochondrial | PDHX | 0.60 | 2.1 × 10−6 | 0.66 | 1.4 × 10−3 |
Q14693-1 | Phosphatidate phosphatase LPIN1 | LPIN1 | 0.61 | 2.8 × 10−3 | 0.39 | 2.7 × 10−4 |
Q96EM0 | Trans-3-Hydroxy-L-proline dehydratase | L3HYPDH | 0.64 | 1.9 × 10−4 | 0.31 | 1.1 × 10−4 |
P13674-1 | Prolyl 4-hydroxylase subunit alpha-1 | P4HA1 | 0.64 | 3.2 × 10−5 | 0.62 | 1.2 × 10−5 |
Q969N2 | GPI transamidase component PIG-T | PIGT | 0.65 | 3.3 × 10−3 | 0.44 | 3.5 × 10−4 |
P53701 | Cytochrome c-type heme lyase | HCCS | 0.65 | 8.1 × 10−4 | 0.38 | 4.2 × 10−5 |
Q7L5N7 | Lysophosphatidylcholine acyltransferase 2 | LPCAT2 | 0.65 | 2.3 × 10−5 | 0.58 | 7.8 × 10−6 |
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Kyuno, D.; Asano, H.; Okumura, R.; Takasawa, K.; Takasawa, A.; Konno, T.; Nakamori, Y.; Magara, K.; Ono, Y.; Imamura, M.; et al. The Role of Claudin-1 in Enhancing Pancreatic Cancer Aggressiveness and Drug Resistance via Metabolic Pathway Modulation. Cancers 2025, 17, 1469. https://doi.org/10.3390/cancers17091469
Kyuno D, Asano H, Okumura R, Takasawa K, Takasawa A, Konno T, Nakamori Y, Magara K, Ono Y, Imamura M, et al. The Role of Claudin-1 in Enhancing Pancreatic Cancer Aggressiveness and Drug Resistance via Metabolic Pathway Modulation. Cancers. 2025; 17(9):1469. https://doi.org/10.3390/cancers17091469
Chicago/Turabian StyleKyuno, Daisuke, Hinae Asano, Reona Okumura, Kumi Takasawa, Akira Takasawa, Takumi Konno, Yuna Nakamori, Kazufumi Magara, Yusuke Ono, Masafumi Imamura, and et al. 2025. "The Role of Claudin-1 in Enhancing Pancreatic Cancer Aggressiveness and Drug Resistance via Metabolic Pathway Modulation" Cancers 17, no. 9: 1469. https://doi.org/10.3390/cancers17091469
APA StyleKyuno, D., Asano, H., Okumura, R., Takasawa, K., Takasawa, A., Konno, T., Nakamori, Y., Magara, K., Ono, Y., Imamura, M., Kimura, Y., Kojima, T., & Osanai, M. (2025). The Role of Claudin-1 in Enhancing Pancreatic Cancer Aggressiveness and Drug Resistance via Metabolic Pathway Modulation. Cancers, 17(9), 1469. https://doi.org/10.3390/cancers17091469