Research progress on cholesterol metabolism in the occurrence, development, and diagnosis of pancreatic ductal adenocarcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Xiaofeng , HOU Shengzhong , HUANG Xing ,  TIAN Bole

Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

TIAN Bole, Email: hxtbl0338@163.com

Keywords：

pancreatic ductal adenocarcinoma; cholesterol metabolism; targeted therapy

DOI：

10.7507/1007-9424.202312071

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the remodeling of cholesterol metabolism in the occurrence and progression of pancreatic ductal adenocarcinoma (PDAC), and to review the research progress on targeted cholesterol metabolism in the treatment of PDAC. Method Relevant literatures on cholesterol metabolism in the occurrence, development, and diagnosis and treatment of PDAC in recent years were searched and reviewed. Results Metabolites of PDAC tumor cells affected the expression of oncogenes or tumor suppressor genes. Signaling regulation within tumor cells affects cholesterol metabolism, characterized by increased de novo cholesterol synthesis and esterification, and reduced efflux. Tumor cells also regulated tumor immune microenvironment or tumor stroma formation through cholesterol metabolism. Inhibiting cholesterol metabolism could suppress the proliferation, invasion and migration of PDAC tumor cells, and combination therapy targeting cholesterol metabolism had a synergistic anti-PDAC effect. Conclusions Remodeling of cholesterol metabolism occurs in both PDAC tumor cells and the tumor microenvironment, and is closely related to the occurrence, development, invasion, metastasis, and treatment response of PDAC. Targeting cholesterol metabolism or combined application with chemotherapy drugs can have anticancer effects. However, more research is needed to support the translation of cholesterol metabolism regulation into clinical treatment applications.

Citation： LIU Xiaofeng, HOU Shengzhong, HUANG Xing, TIAN Bole. Research progress on cholesterol metabolism in the occurrence, development, and diagnosis of pancreatic ductal adenocarcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2024, 31(6): 754-760. doi: 10.7507/1007-9424.202312071 Copy

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2.	Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
3.	Park W, Chawla A, O’Reilly EM. Pancreatic cancer: a review. JAMA, 2021, 326(9): 851-862.
4.	Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33.
5.	Wood LD, Canto MI, Jaffee EM, et al. Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment. Gastroenterology, 2022, 163(2): 386-402.
6.	Abdalkareem Jasim S, Kzar HH, Haider Hamad M, et al. The emerging role of 27-hydroxycholesterol in cancer development and progression: An update. Int Immunopharmacol, 2022, 110: 109074. doi: 10.1016/j.intimp.2022.109074.
7.	Wang R, Liu Z, Fan Z, et al. Lipid metabolism reprogramming of CD8⁺ T cell and therapeutic implications in cancer. Cancer Lett, 2023, 567: 216267. doi: 10.1016/j.canlet.2023.216267.
8.	Sirtori CR, Corsini A, Ruscica M. The role of high-density lipoprotein cholesterol in 2022. Curr Atheroscler Rep, 2022, 24(5): 365-377.
9.	Gu Q, Yang X, Lv J, et al. AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate. Science, 2019, 363(6431): 1085-1088.
10.	Wang JQ, Li LL, Hu A, et al. Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion. Nature, 2022, 608(7922): 413-420.
11.	Wang QL, Khil J, Hong S, et al. Temporal association of total serum cholesterol and pancreatic cancer incidence. Nutrients, 2022, 14(22): 4938. doi: 10.3390/nu14224938.
12.	Khan S, Al Heraki S, Kupec JT. Noninvasive models screen new-onset diabetics at low risk of early-onset pancreatic cancer. Pancreas, 2021, 50(9): 1326-1330.
13.	Boursi B, Finkelman B, Giantonio BJ, et al. A clinical prediction model to assess risk for pancreatic cancer among patients with prediabetes. Eur J Gastroenterol Hepatol, 2022, 34(1): 33-38.
14.	Qiu G, Zhang L, Gu Z, et al. Preoperative alkaline phosphatase-to-cholesterol ratio as a predictor of overall survival in pancreatic ductal adenocarcinoma patients undergoing radical pancreaticoduodenectomy. Med Sci Monit, 2021, 7: e931868. doi: 10.12659/MSM.931868.
15.	Wang F, Huang L, Zhang J, et al. Dyslipidemia in Chinese pancreatic cancer patients: A two-center retrospective study. J Cancer, 2021, 12(17): 5338-5344.
16.	Gunda V, Genaro-Mattos TC, Kaushal JB, et al. Ubiquitous aberration in cholesterol metabolism across pancreatic ductal adenocarcinoma. Metabolites, 2022, 12(1): 47. doi: 10.3390/metabo12010047.
17.	Xu R, Song J, Ruze R, et al. SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway. Cell Death Dis, 2023, 14(8): 497. doi: 10.1038/s41419-023-05987-7.
18.	Pirhonen J, Szkalisity Á, Hagström J, et al. Lipid metabolic reprogramming extends beyond histologic tumor demarcations in operable human pancreatic cancer. Cancer Res, 2022, 82(21): 3932-3949.
19.	You W, Ke J, Chen Y, et al. SQLE, a key enzyme in cholesterol metabolism, correlates with tumor immune infiltration and immunotherapy outcome of pancreatic adenocarcinoma. Front Immunol, 2022, 13: 864244. doi: 10.3389/fimmu.2022.864244.
20.	Li Y, Amrutkar M, Finstadsveen AV, et al. Fatty acids abrogate the growth-suppressive effects induced by inhibition of cholesterol flux in pancreatic cancer cells. Cancer Cell Int, 2023, 23(1): 276. doi: 10.1186/s12935-023-03138-8.
21.	Wang L, Ruan Y, Wu X, et al. LncRNA ZFAS1 promotes HMGCR mRNA stabilization via binding U2AF2 to modulate pancreatic carcinoma lipometabolism. J Immunol Res, 2022, 2022: 4163198. doi: 10.1155/2022/4163198.
22.	Zhao F, Huang Y, Zhang Y, et al. SQLE inhibition suppresses the development of pancreatic ductal adenocarcinoma and enhances its sensitivity to chemotherapeutic agents in vitro. Mol Biol Rep, 2022, 49(7): 6613-6621.
23.	Ding Z, Gu Y, Huang D, et al. Cholesterol biosynthesis inhibitor RO 48-8071 inhibits pancreatic ductal adenocarcinoma cell viability by deactivating the JNK and ERK/MAPK signaling pathway. Mol Med Rep, 2021, 24(6): 828. doi: 10.3892/mmr.2021.12468.
24.	Zheng S, Lin J, Pang Z, et al. Aberrant cholesterol metabolism and Wnt/β-catenin signaling coalesce via frizzled5 in supporting cancer growth. Adv Sci (Weinh), 2022, 9(28): e2200750. doi: 10.1002/advs.202200750.
25.	Alexander JI, Martinez E, Vargas A, et al. Cholesterol and CDON regulate sonic hedgehog release from pancreatic cancer cells. J Pancreat Cancer, 2021, 7(1): 39-47.
26.	McBrearty N, Cho C, Chen J, et al. Tumor-suppressive and immune-stimulating roles of cholesterol 25-hydroxylase in pancreatic cancer cells. Mol Cancer Res, 2023, 21(3): 228-239.
27.	Huang CT, Liang YJ. Anti-tumor effect of statin on pancreatic adenocarcinoma: From concept to precision medicine. World J Clin Cases, 2021, 9(18): 4500-4505.
28.	Ako S, Teper Y, Ye L, et al. Statins inhibit inflammatory cytokine production by macrophages and acinar-to-ductal metaplasia of pancreatic cells. Gastro Hep Adv, 2022, 1(4): 640-651.
29.	Yin Y, Liu L, Zhao Z, et al. Simvastatin inhibits sonic hedgehog signaling and stemness features of pancreatic cancer. Cancer Lett, 2018, 426: 14-24.
30.	Uemura N, Hayashi H, Liu Z, et al. Statins exert anti-growth effects by suppressing YAP/TAZ expressions via JNK signal activation and eliminate the immune suppression by downregulating PD-L1 expression in pancreatic cancer. Am J Cancer Res, 2023, 13(5): 2041-2054.
31.	Minz AP, Mohapatra D, Dutta M, et al. Statins abrogate gemcitabine-induced PD-L1 expression in pancreatic cancer-associated fibroblasts and cancer cells with improved therapeutic outcome. Cancer Immunol Immunother, 2023, 72(12): 4261-4278.
32.	Teper Y, Ye L, Waldron RT, et al. Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice. Sci Rep, 2023, 13(1): 16144. doi: 10.1038/s41598-023-43498-9.
33.	Chen YH, Huang YC, Yang SF, et al. Pitavastatin and metformin synergistically activate apoptosis and autophagy in pancreatic cancer cells. Environ Toxicol, 2021, 36(8): 1491-1503.
34.	Gyoten M, Luo Y, Fujiwara-Tani R, et al. Lovastatin treatment inducing apoptosis in human pancreatic cancer cells by inhibiting cholesterol rafts in plasma membrane and mitochondria. Int J Mol Sci, 2023, 24(23): 16814. doi: 10.3390/ijms242316814.
35.	Rimpelová S, Kolář M, Strnad H, et al. Comparison of transcriptomic profiles of MiaPaCa-2 pancreatic cancer cells treated with different statins. Molecules, 2021, 26(12): 3528. doi: 10.3390/molecules26123528.
36.	Seshacharyulu P, Halder S, Nimmakayala R, et al. Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling. EBioMedicine, 2022, 75: 103772. doi: 10.1016/j.ebiom.2021.103772.
37.	Benitez-Amaro A, Martínez-Bosch N, Manero-Rupérez N, et al. Peptides against low density lipoprotein (LDL) aggregation inhibit intracellular cholesteryl ester loading and proliferation of pancreatic tumor cells. Cancers (Basel), 2022, 14(4): 890. doi: 10.3390/cancers14040890.
38.	Liu C, Chen J, Chen H, et al. PCSK9 inhibition: from current advances to evolving future. Cells, 2022, 11(19): 2972. doi: 10.3390/cells11192972.
39.	Jung YY, Ko JH, Um JY, et al. LDL cholesterol promotes the proliferation of prostate and pancreatic cancer cells by activating the STAT3 pathway. J Cell Physiol, 2021, 236(7): 5253-5264.
40.	Kuo YC, Kou HW, Hsu CP, et al. Identification and clinical significance of pancreatic cancer stem cells and their chemotherapeutic drug resistance. Int J Mol Sci, 2023, 24(8): 7331. doi: 10.3390/ijms24087331.
41.	Muñoz Velasco R, Jiménez Sánchez P, García García A, et al. Targeting BPTF sensitizes pancreatic ductal adenocarcinoma to chemotherapy by repressing ABC-transporters and impairing multidrug resistance (MDR). Cancers (Basel), 2022, 14(6): 1518. doi: 10.3390/cancers14061518.
42.	Gu J, Huang W, Wang X, et al. Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer. Mol Cancer, 2022, 21(1): 112. doi: 10.1186/s12943-022-01587-9.
43.	Cervenkova L, Palek R, Moulisova V, et al. Protein expression and localization of ABC transporters in pancreatic adenocarcinoma: Prognostic role of ABCC8. Pancreatology, 2023, 23(8): 978-987.
44.	Oberle R, Kührer K, Österreicher T, et al. The HDL particle composition determines its antitumor activity in pancreatic cancer. Life Sci Alliance, 2022, 5(9): e202101317. doi: 10.26508/lsa.202101317.
45.	Oni TE, Biffi G, Baker LA, et al. SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. J Exp Med, 2020, 217(9): e20192389. doi: 10.1084/jem.20192389.
46.	Li J, Gu D, Lee SS, et al. Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene, 2016, 35(50): 6378-6388.
47.	Yu S, Wang L, Che D, et al. Targeting CRABP-II overcomes pancreatic cancer drug resistance by reversing lipid raft cholesterol accumulation and AKT survival signaling. J Exp Clin Cancer Res, 2022, 41(1): 88. doi: 10.1186/s13046-022-02261-0.
48.	Gu X, Zhu Q, Tian G, et al. KIF11 manipulates SREBP2-dependent mevalonate cross talk to promote tumor progression in pancreatic ductal adenocarcinoma. Cancer Med, 2022, 11(17): 3282-3295.
49.	Zhang D, Lu P, Zhu K, et al. TFCP2 overcomes senescence by cooperating with SREBP2 to activate cholesterol synthesis in pancreatic cancer. Front Oncol, 2021, 11: 724437. doi: 10.3389/fonc.2021.724437.
50.	Kim Y, Jee W, An EJ, et al. Timosaponin A3 inhibits palmitate and stearate through suppression of SREBP-1 in pancreatic cancer. Pharmaceutics, 2022, 14(5): 945. doi: 10.3390/pharmaceutics14050945.
51.	Kandhari K, Paudel S, Raina K, et al. Comparative pre-clinical efficacy of Chinese and indian cultivars of bitter melon (Momordica charantia) against pancreatic cancer. J Cancer Prev, 2021, 26(4): 266-276.
52.	Kemp SB, Carpenter ES, Steele NG, et al. Apolipoprotein E promotes immune suppression in pancreatic cancer through NF-κB-mediated production of CXCL1. Cancer Res, 2021, 81(16): 4305-4318.
53.	Herremans KM, Szymkiewicz DD, Riner AN, et al. The interleukin-1 axis and the tumor immune microenvironment in pancreatic ductal adenocarcinoma. Neoplasia, 2022, 28: 100789. doi: 10.1016/j.neo.2022.100789.
54.	Yan C, Zheng L, Jiang S, et al. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity. Cancer Cell, 2023, 41(7): 1276-1293.
55.	Wu B, Shen W, Wang X, et al. Plasma lipid levels are associated with the CD8⁺ T-cell infiltration and prognosis of patients with pancreatic cancer. Cancer Med, 2023, 12(13): 14138-14148.

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin, 2024, 74(1): 12-49.
2. Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
3. Park W, Chawla A, O’Reilly EM. Pancreatic cancer: a review. JAMA, 2021, 326(9): 851-862.
4. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33.
5. Wood LD, Canto MI, Jaffee EM, et al. Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment. Gastroenterology, 2022, 163(2): 386-402.
6. Abdalkareem Jasim S, Kzar HH, Haider Hamad M, et al. The emerging role of 27-hydroxycholesterol in cancer development and progression: An update. Int Immunopharmacol, 2022, 110: 109074. doi: 10.1016/j.intimp.2022.109074.
7. Wang R, Liu Z, Fan Z, et al. Lipid metabolism reprogramming of CD8⁺ T cell and therapeutic implications in cancer. Cancer Lett, 2023, 567: 216267. doi: 10.1016/j.canlet.2023.216267.
8. Sirtori CR, Corsini A, Ruscica M. The role of high-density lipoprotein cholesterol in 2022. Curr Atheroscler Rep, 2022, 24(5): 365-377.
9. Gu Q, Yang X, Lv J, et al. AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate. Science, 2019, 363(6431): 1085-1088.
10. Wang JQ, Li LL, Hu A, et al. Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion. Nature, 2022, 608(7922): 413-420.
11. Wang QL, Khil J, Hong S, et al. Temporal association of total serum cholesterol and pancreatic cancer incidence. Nutrients, 2022, 14(22): 4938. doi: 10.3390/nu14224938.
12. Khan S, Al Heraki S, Kupec JT. Noninvasive models screen new-onset diabetics at low risk of early-onset pancreatic cancer. Pancreas, 2021, 50(9): 1326-1330.
13. Boursi B, Finkelman B, Giantonio BJ, et al. A clinical prediction model to assess risk for pancreatic cancer among patients with prediabetes. Eur J Gastroenterol Hepatol, 2022, 34(1): 33-38.
14. Qiu G, Zhang L, Gu Z, et al. Preoperative alkaline phosphatase-to-cholesterol ratio as a predictor of overall survival in pancreatic ductal adenocarcinoma patients undergoing radical pancreaticoduodenectomy. Med Sci Monit, 2021, 7: e931868. doi: 10.12659/MSM.931868.
15. Wang F, Huang L, Zhang J, et al. Dyslipidemia in Chinese pancreatic cancer patients: A two-center retrospective study. J Cancer, 2021, 12(17): 5338-5344.
16. Gunda V, Genaro-Mattos TC, Kaushal JB, et al. Ubiquitous aberration in cholesterol metabolism across pancreatic ductal adenocarcinoma. Metabolites, 2022, 12(1): 47. doi: 10.3390/metabo12010047.
17. Xu R, Song J, Ruze R, et al. SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway. Cell Death Dis, 2023, 14(8): 497. doi: 10.1038/s41419-023-05987-7.
18. Pirhonen J, Szkalisity Á, Hagström J, et al. Lipid metabolic reprogramming extends beyond histologic tumor demarcations in operable human pancreatic cancer. Cancer Res, 2022, 82(21): 3932-3949.
19. You W, Ke J, Chen Y, et al. SQLE, a key enzyme in cholesterol metabolism, correlates with tumor immune infiltration and immunotherapy outcome of pancreatic adenocarcinoma. Front Immunol, 2022, 13: 864244. doi: 10.3389/fimmu.2022.864244.
20. Li Y, Amrutkar M, Finstadsveen AV, et al. Fatty acids abrogate the growth-suppressive effects induced by inhibition of cholesterol flux in pancreatic cancer cells. Cancer Cell Int, 2023, 23(1): 276. doi: 10.1186/s12935-023-03138-8.
21. Wang L, Ruan Y, Wu X, et al. LncRNA ZFAS1 promotes HMGCR mRNA stabilization via binding U2AF2 to modulate pancreatic carcinoma lipometabolism. J Immunol Res, 2022, 2022: 4163198. doi: 10.1155/2022/4163198.
22. Zhao F, Huang Y, Zhang Y, et al. SQLE inhibition suppresses the development of pancreatic ductal adenocarcinoma and enhances its sensitivity to chemotherapeutic agents in vitro. Mol Biol Rep, 2022, 49(7): 6613-6621.
23. Ding Z, Gu Y, Huang D, et al. Cholesterol biosynthesis inhibitor RO 48-8071 inhibits pancreatic ductal adenocarcinoma cell viability by deactivating the JNK and ERK/MAPK signaling pathway. Mol Med Rep, 2021, 24(6): 828. doi: 10.3892/mmr.2021.12468.
24. Zheng S, Lin J, Pang Z, et al. Aberrant cholesterol metabolism and Wnt/β-catenin signaling coalesce via frizzled5 in supporting cancer growth. Adv Sci (Weinh), 2022, 9(28): e2200750. doi: 10.1002/advs.202200750.
25. Alexander JI, Martinez E, Vargas A, et al. Cholesterol and CDON regulate sonic hedgehog release from pancreatic cancer cells. J Pancreat Cancer, 2021, 7(1): 39-47.
26. McBrearty N, Cho C, Chen J, et al. Tumor-suppressive and immune-stimulating roles of cholesterol 25-hydroxylase in pancreatic cancer cells. Mol Cancer Res, 2023, 21(3): 228-239.
27. Huang CT, Liang YJ. Anti-tumor effect of statin on pancreatic adenocarcinoma: From concept to precision medicine. World J Clin Cases, 2021, 9(18): 4500-4505.
28. Ako S, Teper Y, Ye L, et al. Statins inhibit inflammatory cytokine production by macrophages and acinar-to-ductal metaplasia of pancreatic cells. Gastro Hep Adv, 2022, 1(4): 640-651.
29. Yin Y, Liu L, Zhao Z, et al. Simvastatin inhibits sonic hedgehog signaling and stemness features of pancreatic cancer. Cancer Lett, 2018, 426: 14-24.
30. Uemura N, Hayashi H, Liu Z, et al. Statins exert anti-growth effects by suppressing YAP/TAZ expressions via JNK signal activation and eliminate the immune suppression by downregulating PD-L1 expression in pancreatic cancer. Am J Cancer Res, 2023, 13(5): 2041-2054.
31. Minz AP, Mohapatra D, Dutta M, et al. Statins abrogate gemcitabine-induced PD-L1 expression in pancreatic cancer-associated fibroblasts and cancer cells with improved therapeutic outcome. Cancer Immunol Immunother, 2023, 72(12): 4261-4278.
32. Teper Y, Ye L, Waldron RT, et al. Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice. Sci Rep, 2023, 13(1): 16144. doi: 10.1038/s41598-023-43498-9.
33. Chen YH, Huang YC, Yang SF, et al. Pitavastatin and metformin synergistically activate apoptosis and autophagy in pancreatic cancer cells. Environ Toxicol, 2021, 36(8): 1491-1503.
34. Gyoten M, Luo Y, Fujiwara-Tani R, et al. Lovastatin treatment inducing apoptosis in human pancreatic cancer cells by inhibiting cholesterol rafts in plasma membrane and mitochondria. Int J Mol Sci, 2023, 24(23): 16814. doi: 10.3390/ijms242316814.
35. Rimpelová S, Kolář M, Strnad H, et al. Comparison of transcriptomic profiles of MiaPaCa-2 pancreatic cancer cells treated with different statins. Molecules, 2021, 26(12): 3528. doi: 10.3390/molecules26123528.
36. Seshacharyulu P, Halder S, Nimmakayala R, et al. Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling. EBioMedicine, 2022, 75: 103772. doi: 10.1016/j.ebiom.2021.103772.
37. Benitez-Amaro A, Martínez-Bosch N, Manero-Rupérez N, et al. Peptides against low density lipoprotein (LDL) aggregation inhibit intracellular cholesteryl ester loading and proliferation of pancreatic tumor cells. Cancers (Basel), 2022, 14(4): 890. doi: 10.3390/cancers14040890.
38. Liu C, Chen J, Chen H, et al. PCSK9 inhibition: from current advances to evolving future. Cells, 2022, 11(19): 2972. doi: 10.3390/cells11192972.
39. Jung YY, Ko JH, Um JY, et al. LDL cholesterol promotes the proliferation of prostate and pancreatic cancer cells by activating the STAT3 pathway. J Cell Physiol, 2021, 236(7): 5253-5264.
40. Kuo YC, Kou HW, Hsu CP, et al. Identification and clinical significance of pancreatic cancer stem cells and their chemotherapeutic drug resistance. Int J Mol Sci, 2023, 24(8): 7331. doi: 10.3390/ijms24087331.
41. Muñoz Velasco R, Jiménez Sánchez P, García García A, et al. Targeting BPTF sensitizes pancreatic ductal adenocarcinoma to chemotherapy by repressing ABC-transporters and impairing multidrug resistance (MDR). Cancers (Basel), 2022, 14(6): 1518. doi: 10.3390/cancers14061518.
42. Gu J, Huang W, Wang X, et al. Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer. Mol Cancer, 2022, 21(1): 112. doi: 10.1186/s12943-022-01587-9.
43. Cervenkova L, Palek R, Moulisova V, et al. Protein expression and localization of ABC transporters in pancreatic adenocarcinoma: Prognostic role of ABCC8. Pancreatology, 2023, 23(8): 978-987.
44. Oberle R, Kührer K, Österreicher T, et al. The HDL particle composition determines its antitumor activity in pancreatic cancer. Life Sci Alliance, 2022, 5(9): e202101317. doi: 10.26508/lsa.202101317.
45. Oni TE, Biffi G, Baker LA, et al. SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. J Exp Med, 2020, 217(9): e20192389. doi: 10.1084/jem.20192389.
46. Li J, Gu D, Lee SS, et al. Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene, 2016, 35(50): 6378-6388.
47. Yu S, Wang L, Che D, et al. Targeting CRABP-II overcomes pancreatic cancer drug resistance by reversing lipid raft cholesterol accumulation and AKT survival signaling. J Exp Clin Cancer Res, 2022, 41(1): 88. doi: 10.1186/s13046-022-02261-0.
48. Gu X, Zhu Q, Tian G, et al. KIF11 manipulates SREBP2-dependent mevalonate cross talk to promote tumor progression in pancreatic ductal adenocarcinoma. Cancer Med, 2022, 11(17): 3282-3295.
49. Zhang D, Lu P, Zhu K, et al. TFCP2 overcomes senescence by cooperating with SREBP2 to activate cholesterol synthesis in pancreatic cancer. Front Oncol, 2021, 11: 724437. doi: 10.3389/fonc.2021.724437.
50. Kim Y, Jee W, An EJ, et al. Timosaponin A3 inhibits palmitate and stearate through suppression of SREBP-1 in pancreatic cancer. Pharmaceutics, 2022, 14(5): 945. doi: 10.3390/pharmaceutics14050945.
51. Kandhari K, Paudel S, Raina K, et al. Comparative pre-clinical efficacy of Chinese and indian cultivars of bitter melon (Momordica charantia) against pancreatic cancer. J Cancer Prev, 2021, 26(4): 266-276.
52. Kemp SB, Carpenter ES, Steele NG, et al. Apolipoprotein E promotes immune suppression in pancreatic cancer through NF-κB-mediated production of CXCL1. Cancer Res, 2021, 81(16): 4305-4318.
53. Herremans KM, Szymkiewicz DD, Riner AN, et al. The interleukin-1 axis and the tumor immune microenvironment in pancreatic ductal adenocarcinoma. Neoplasia, 2022, 28: 100789. doi: 10.1016/j.neo.2022.100789.
54. Yan C, Zheng L, Jiang S, et al. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity. Cancer Cell, 2023, 41(7): 1276-1293.
55. Wu B, Shen W, Wang X, et al. Plasma lipid levels are associated with the CD8⁺ T-cell infiltration and prognosis of patients with pancreatic cancer. Cancer Med, 2023, 12(13): 14138-14148.

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Research progress on cholesterol metabolism in the occurrence, development, and diagnosis of pancreatic ductal adenocarcinoma

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