Advances in Surgical Sciences

Submit a Manuscript

Publishing with us to make your research visible to the widest possible audience.

Propose a Special Issue

Building a community of authors and readers to discuss the latest research and develop new ideas.

The Potential Role of circRNAs Action on Classic Pathways of Signal Transduction PI3K/AKT in Treatment of Pancreatic Cancer

Cancer is a highly complex disease characterized by diverse clinical manifestations and intricate etiology, involving DNA impairment, RNA dysregulation, protein dysfunction, and other contributing factors. The progression, invasion, angiogenesis, and metastasis of cancer are regulated by a multitude of pathways and agents that influence crucial cellular processes like apoptosis, cell survival, and gene expression. Among these pathways, the PI3K/AKT signaling pathway has emerged as a pivotal player, interacting with various intracellular agents including proteins, microRNAs (miRNAs), and circular RNAs (circRNAs). CircRNAs, in particular, form intricate networks that play essential roles in tumor development, transforming previous perspectives on cancer incidence, growth, metastasis, as well as diagnosis, prognosis, and treatment. A deeper understanding of these intricate intracellular interactions holds the potential for improved cancer control. In this comprehensive review, we explore the dynamic crosstalk between the PI3K/AKT signaling pathway, tumor initiation, and circRNAs. We delve into the intricate mechanisms through which circRNAs modulate cancer progression, invasion, and metastasis, shedding light on their multifaceted roles in shaping the cancer landscape. Furthermore, we discuss the potential of circRNAs as promising therapeutic targets and diagnostic biomarkers for cancer management. By elucidating the complex interplay between PI3K/AKT signaling, tumor biology, and circRNAs, we pave the way for the development of innovative therapeutic strategies in cancer treatment. This review underscores the importance of unraveling the intricate molecular networks governing cancer pathogenesis. By elucidating the involvement of the PI3K/AKT pathway and its intricate interplay with circRNAs, we contribute to a deeper understanding of the molecular underpinnings of cancer. Ultimately, this knowledge can guide the development of novel therapeutic interventions and diagnostic approaches for improved cancer management. As we gain a more comprehensive understanding of the complex interplay between the PI3K/AKT signaling pathway, tumor initiation, and circRNAs, we unlock the potential to revolutionize cancer treatment and pave the way for more personalized and effective therapeutic strategies.

MicroRNAs, Circular RNAs, Pancreatic Cancer, PI3K/AKT Signaling Pathway

Zahra Taheri, Nafise Noroozi, Mahsa M. Amoli. (2023). The Potential Role of circRNAs Action on Classic Pathways of Signal Transduction PI3K/AKT in Treatment of Pancreatic Cancer. Advances in Surgical Sciences, 11(1), 5-13.

Copyright © 2023 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Andrei L, Kasas S, Garrido IO, Stanković T, Korsnes MS, Vaclavikova R, et al. Advanced technological tools to study multidrug resistance in cancer. Drug Resistance Updates. 2020; 48: 100658.
2. Gapstur SM, Drope JM, Jacobs EJ, Teras LR, McCullough ML, Douglas CE, et al. A blueprint for the primary prevention of cancer: targeting established, modifiable risk factors. CA: a cancer journal for clinicians. 2018; 68 (6): 446-70.
3. Martínez-Jiménez F, Muiños F, Sentís I, Deu-Pons J, Reyes-Salazar I, Arnedo-Pac C, et al. A compendium of mutational cancer driver genes. Nature Reviews Cancer. 2020; 20 (10): 555-72.
4. Alcaraz KI, Wiedt TL, Daniels EC, Yabroff KR, Guerra CE, Wender RC. Understanding and addressing social determinants to advance cancer health equity in the United States: a blueprint for practice, research, and policy. CA: a cancer journal for clinicians. 2020; 70 (1): 31-46.
5. Yabroff KR, Gansler T, Wender RC, Cullen KJ, Brawley OW. Minimizing the burden of cancer in the United States: Goals for a high-performing health care system. CA: a cancer journal for clinicians. 2019; 69 (3): 166-83.
6. Bright CJ, Reulen RC, Winter DL, Stark DP, McCabe MG, Edgar AB, et al. Risk of subsequent primary neoplasms in survivors of adolescent and young adult cancer (Teenage and Young Adult Cancer Survivor Study): a population-based, cohort study. The Lancet Oncology. 2019; 20 (4): 531-45.
7. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nature reviews Drug discovery. 2017; 16 (3): 203-22.
8. Yin H, Xue W, Anderson DG. CRISPR–Cas: a tool for cancer research and therapeutics. Nature reviews Clinical oncology. 2019; 16 (5): 281-95.
9. Akhave N, Biter A, Hong D. Mechanisms of Resistance to KRAS (G12C)-Targeted Therapy. Cancer Discov. 2021; 11: 1345–1352. doi: 10.1158/2159-8290. CD-20-1616. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar].
10. Evans ER, Bugga P, Asthana V, Drezek R. Metallic nanoparticles for cancer immunotherapy. Materials Today. 2018; 21 (6): 673-85.
11. Aufiero S, Reckman YJ, Pinto YM, Creemers EE. Circular RNAs open a new chapter in cardiovascular biology. Nature Reviews Cardiology. 2019; 16 (8): 503-14.
12. Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, et al. The landscape of circular RNA in cancer. Cell. 2019; 176 (4): 869-81. e13.
13. Wen G, Zhou T, Gu W. The potential of using blood circular RNA as liquid biopsy biomarker for human diseases. Protein & cell. 2021; 12 (12): 911-46.
14. Chen YG, Chen R, Ahmad S, Verma R, Kasturi SP, Amaya L, et al. N6-methyladenosine modification controls circular RNA immunity. Molecular cell. 2019; 76 (1): 96-109. e9.
15. Legnini I, Di Timoteo G, Rossi F, Morlando M, Briganti F, Sthandier O, et al. Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Molecular cell. 2017; 66 (1): 22-37. e9.
16. Liu Z, Wang Q, Wang X, Xu Z, Wei X, Li J. Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5. Cell death discovery. 2020; 6 (1): 1-11.
17. Bilanges B, Posor Y, Vanhaesebroeck B. PI3K isoforms in cell signalling and vesicle trafficking. Nature reviews Molecular cell biology. 2019; 20 (9): 515-34.
18. Molinaro A, Becattini B, Mazzoli A, Bleve A, Radici L, Maxvall I, et al. Insulin-driven PI3K-AKT signaling in the hepatocyte is mediated by redundant PI3Kα and PI3Kβ activities and is promoted by RAS. Cell Metabolism. 2019; 29 (6): 1400-9. e5.
19. Hopkins BD, Goncalves MD, Cantley LC. Insulin–PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nature Reviews Endocrinology. 2020; 16 (5): 276-83.
20. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017; 170 (4): 605-35.
21. Hoxhaj G, Manning BD. The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism. Nature Reviews Cancer. 2020; 20 (2): 74-88.
22. Hanker AB, Kaklamani V, Arteaga CL. Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid TumorsWhat Limits the Success of PI3K Inhibitors? Cancer discovery. 2019; 9 (4): 482-91.
23. Vara JÁF, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer treatment reviews. 2004; 30 (2): 193-204.
24. Gulluni F, De Santis MC, Margaria JP, Martini M, Hirsch E. Class II PI3K functions in cell biology and disease. Trends in cell biology. 2019; 29 (4): 339-59.
25. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nature reviews Molecular cell biology. 2010; 11 (5): 329-41.
26. El Motiam A, de la Cruz-Herrera CF, Vidal S, Seoane R, Baz-Martínez M, Bouzaher YH, et al. SUMOylation modulates the stability and function of PI3K-p110β. Cellular and Molecular Life Sciences. 2021; 78 (8): 4053-65.
27. De la Cruz-Herrera C, Baz-Martínez M, Lang V, El Motiam A, Barbazán J, Couceiro R, et al. Conjugation of SUMO to p85 leads to a novel mechanism of PI3K regulation. Oncogene. 2016; 35 (22): 2873-80.
28. Murillo MM, Zelenay S, Nye E, Castellano E, Lassailly F, Stamp G, et al. RAS interaction with PI3K p110α is required for tumor-induced angiogenesis. The Journal of clinical investigation. 2014; 124 (8): 3601-11.
29. Tamaskovic R, Schwill M, Nagy-Davidescu G, Jost C, Schaefer DC, Verdurmen WP, et al. Intermolecular biparatopic trapping of ErbB2 prevents compensatory activation of PI3K/AKT via RAS–p110 crosstalk. Nature Communications. 2016; 7 (1): 1-18.
30. Johnson C, Chun-Jen Lin C, Stern M. Ras-dependent and Ras-independent effects of PI3K in Drosophila motor neurons. Genes, Brain and Behavior. 2012; 11 (7): 848-58.
31. Bresnick AR, Backer JM. PI3K β—A Versatile Transducer for GPCR, RTK, and Small GTPase Signaling. Endocrinology. 2019; 160 (3): 536-55.
32. Oudit GY, Sun H, Kerfant B-G, Crackower MA, Penninger JM, Backx PH. The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. Journal of molecular and cellular cardiology. 2004; 37 (2): 449-71.
33. Houslay DM, Anderson KE, Chessa T, Kulkarni S, Fritsch R, Downward J, et al. Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells. Science signaling. 2016; 9 (441): ra82-ra.
34. Zhu F, Guo H, Bates PD, Zhang S, Zhang H, Nomie KJ, et al. PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cells. Leukemia. 2019; 33 (12): 2898-911.
35. Duan Y, Haybaeck J, Yang Z. Therapeutic potential of PI3K/AKT/mTOR pathway in gastrointestinal stromal tumors: rationale and progress. Cancers. 2020; 12 (10): 2972.
36. Talbot K, Wang H-Y, Kazi H, Han L-Y, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. The Journal of clinical investigation. 2012; 122 (4): 1316-38.
37. Guo H, German P, Bai S, Barnes S, Guo W, Qi X, et al. The PI3K/AKT pathway and renal cell carcinoma. Journal of genetics and genomics. 2015; 42 (7): 343-53.
38. Yang Q, Jiang W, Hou P, editors. Emerging role of PI3K/AKT in tumor-related epigenetic regulation. Seminars in Cancer biology; 2019: Elsevier.
39. Lien EC, Dibble CC, Toker A. PI3K signaling in cancer: beyond AKT. Current opinion in cell biology. 2017; 45: 62-71.
40. Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Frontiers in molecular neuroscience. 2011; 4: 51.
41. Tian T, Li X, Zhang J. mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. International journal of molecular sciences. 2019; 20 (3): 755.
42. Hanrahan J, Blenis J. Rheb activation of mTOR and S6K1 signaling. Methods in enzymology. 2006; 407: 542-55.
43. Wang Y, Wang Y, Li J, Li J, Che G. Clinical significance of PIK3CA gene in non-small-cell lung cancer: a systematic review and meta-analysis. BioMed research international. 2020; 2020.
44. Miller MS, Maheshwari S, McRobb FM, Kinzler KW, Amzel LM, Vogelstein B, et al. Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design. Bioorganic & medicinal chemistry. 2017; 25 (4): 1481-6.
45. Pothongsrisit S, Pongrakhananon V. Targeting the PI3K/AKT/mTOR signaling pathway in lung cancer: an update regarding potential drugs and natural products. Molecules. 2021; 26 (13): 4100.
46. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017; 168 (6): 960-76.
47. Roshan MK, Soltani A, Soleimani A, Kahkhaie KR, Afshari AR, Soukhtanloo M. Role of AKT and mTOR signaling pathways in the induction of epithelial-mesenchymal transition (EMT) process. Biochimie. 2019; 165: 229-34.
48. Chin YR, Toker A. The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Molecular cell. 2010; 38 (3): 333-44.
49. Hay N. Interplay between FOXO, TOR, and Akt. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2011; 1813 (11): 1965-70.
50. Miyamoto M, Takano M, Iwaya K, Shinomiya N, Kato M, Aoyama T, et al. X-chromosome-linked inhibitor of apoptosis as a key factor for chemoresistance in clear cell carcinoma of the ovary. British journal of cancer. 2014; 110 (12): 2881-6.
51. Zuazo-Gaztelu I, Casanovas O. Unraveling the role of angiogenesis in cancer ecosystems. Frontiers in Oncology. 2018; 8: 248.
52. Sharma A. Chemoresistance in cancer cells: exosomes as potential regulators of therapeutic tumor heterogeneity. Nanomedicine. 2017; 12 (17): 2137-48.
53. Garcia-Mayea Y, Mir C, Masson F, Paciucci R, LLeonart M, editors. Insights into new mechanisms and models of cancer stem cell multidrug resistance. Seminars in cancer biology; 2020: Elsevier.
54. Yang C, Hou A, Yu C, Dai L, Wang W, Zhang K, et al. Kanglaite reverses multidrug resistance of HCC by inducing apoptosis and cell cycle arrest via PI3K/AKT pathway. OncoTargets and therapy. 2018; 11: 983.
55. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP–dependent transporters. Nature reviews cancer. 2002; 2 (1): 48-58.
56. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell metabolism. 2008; 7 (1): 11-20.
57. Zhang X, Ai Z, Chen J, Yi J, Liu Z, Zhao H, et al. Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway. Molecular Medicine Reports. 2017; 15 (4): 1869-76.
58. Soltani A, Torki S, Ghahfarokhi MS, Jami MS, Ghatrehsamani M. Targeting the phosphoinositide 3-kinase/AKT pathways by small molecules and natural compounds as a therapeutic approach for breast cancer cells. Molecular Biology Reports. 2019; 46 (5): 4809-16.
59. Chen Y, Wang T, Du J, Li Y, Wang X, Zhou Y, et al. The critical role of PTEN/PI3K/AKT signaling pathway in shikonin-induced apoptosis and proliferation inhibition of chronic myeloid leukemia. Cellular Physiology and Biochemistry. 2018; 47 (3): 981-93.
60. Wu D-m, Zhang T, Liu Y-b, Deng S-h, Han R, Liu T, et al. The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling. Cell death & disease. 2019; 10 (5): 1-15.
61. Ellis H, Ma CX. PI3K inhibitors in breast cancer therapy. Current oncology reports. 2019; 21 (12): 1-9.
62. Wang D-G, Sun Y-B, Ye F, Li W, Kharbuja P, Gao L, et al. Anti-tumor activity of the X-linked inhibitor of apoptosis (XIAP) inhibitor embelin in gastric cancer cells. Molecular and cellular biochemistry. 2014; 386 (1): 143-52.
63. da Graça Rocha G, Oliveira RR, Kaplan MAC, Gattass CR. 3β-Acetyl tormentic acid reverts MRP1/ABCC1 mediated cancer resistance through modulation of intracellular levels of GSH and inhibition of GST activity. European Journal of Pharmacology. 2014; 741: 140-9.
64. Hu Y, Guo R, Wei J, Zhou Y, Ji W, Liu J, et al. Effects of PI3K inhibitor NVP-BKM120 on overcoming drug resistance and eliminating cancer stem cells in human breast cancer cells. Cell death & disease. 2015; 6 (12): e2020-e.
65. Eberle J. Countering TRAIL resistance in melanoma. Cancers. 2019; 11 (5): 656.
66. Kuznetsov VA, Tang Z, Ivshina AV. Identification of common oncogenic and early developmental pathways in the ovarian carcinomas controlling by distinct prognostically significant microRNA subsets. BMC genomics. 2017; 18 (6): 95-118.
67. Xue C, Li G, Lu J, Li L. Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal Transduction and Targeted Therapy. 2021; 6 (1): 1-17.
68. Patel S, Macaulay K, Woodgett JR. Tissue-specific analysis of glycogen synthase kinase-3α (GSK-3α) in glucose metabolism: effect of strain variation. PLoS One. 2011; 6 (1): e15845.
69. Von Achenbach C, Weller M, Kaulich K, Gramatzki D, Zacher A, Fabbro D, et al. Synergistic growth inhibition mediated by dual PI3K/mTOR pathway targeting and genetic or direct pharmacological AKT inhibition in human glioblastoma models. Journal of neurochemistry. 2020; 153 (4): 510-24.
70. Oh S, Kim H, Nam K, Shin I. Silencing of Glut1 induces chemoresistance via modulation of Akt/GSK-3β/β-catenin/survivin signaling pathway in breast cancer cells. Archives of biochemistry and biophysics. 2017; 636: 110-22.
71. Zhang Z-y, Gao X-h, Ma M-y, Zhao C-l, Zhang Y-l, Guo S-s. CircRNA_101237 promotes NSCLC progression via the miRNA-490-3p/MAPK1 axis. Scientific reports. 2020; 10 (1): 1-10.
72. Zhan W, Liao X, Chen Z, Li L, Tian T, Yu L, et al. Circular RNA hsa_circRNA_103809 promoted hepatocellular carcinoma development by regulating miR-377-3p/FGFR1/ERK axis. Journal of Cellular Physiology. 2020; 235 (2): 1733-45.
73. Kristensen L, Hansen T, Venø M, Kjems J. Circular RNAs in cancer: opportunities and challenges in the field. Oncogene. 2018; 37 (5): 555-65.
74. Yu T, Wang Y, Fan Y, Fang N, Wang T, Xu T, et al. CircRNAs in cancer metabolism: a review. Journal of hematology & oncology. 2019; 12 (1): 1-10.
75. Shin Y-K, Liu Q, Tikoo SK, Babiuk LA, Zhou Y. Influenza A virus NS1 protein activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by direct interaction with the p85 subunit of PI3K. Journal of General Virology. 2007; 88 (1): 13-8.
76. Katan M, Cockcroft S. Phosphatidylinositol (4, 5) bisphosphate: diverse functions at the plasma membrane. Essays in biochemistry. 2020; 64 (3): 513-31.
77. Ishikawa S, Kuno A, Tanno M, Miki T, Kouzu H, Itoh T, et al. Role of connexin-43 in protective PI3K-Akt-GSK-3β signaling in cardiomyocytes. American Journal of Physiology-Heart and Circulatory Physiology. 2012; 302 (12): H2536-H44.
78. Dey JH, Bianchi F, Voshol J, Bonenfant D, Oakeley EJ, Hynes NE. Targeting Fibroblast Growth Factor Receptors Blocks PI3K/AKT Signaling, Induces Apoptosis, and Impairs Mammary Tumor Outgrowth and MetastasisFGFR and Mammary Cancer. Cancer research. 2010; 70 (10): 4151-62.
79. Hofmann BT, Jücker M. Activation of PI3K/Akt signaling by n-terminal SH2 domain mutants of the p85α regulatory subunit of PI3K is enhanced by deletion of its c-terminal SH2 domain. Cellular signalling. 2012; 24 (10): 1950-4.
80. Shi J, Liu C, Chen C, Guo K, Tang Z, Luo Y, et al. Circular RNA circMBOAT2 promotes prostate cancer progression via a miR-1271-5p/mTOR axis. Aging (Albany NY). 2020; 12 (13): 13255.
81. Chen W, Cen S, Zhou X, Yang T, Wu K, Zou L, et al. Circular RNA CircNOLC1, upregulated by NF-KappaB, promotes the progression of prostate cancer via miR-647/PAQR4 axis. Frontiers in Cell and Developmental Biology. 2021; 8: 624764.
82. Salle FG, Le Stang N, Tirode F, Courtiol P, Nicholson AG, Tsao M-S, et al. Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center. JOURNAL OF THORACIC ONCOLOGY. 2020; 15 (6): 1037-53.
83. Yan Z, Xiao Y, Chen Y, Luo G. Screening and identification of epithelial-to-mesenchymal transition-related circRNA and miRNA in prostate cancer. Pathology-Research and Practice. 2020; 216 (2): 152784.
84. Guo X, Zhou Q, Su D, Luo Y, Fu Z, Huang L, et al. Circular RNA circBFAR promotes the progression of pancreatic ductal adenocarcinoma via the miR-34b-5p/MET/Akt axis. Molecular cancer. 2020; 19 (1): 1-18.
85. Kong Y, Li Y, Luo Y, Zhu J, Zheng H, Gao B, et al. circNFIB1 inhibits lymphangiogenesis and lymphatic metastasis via the miR-486-5p/PIK3R1/VEGF-C axis in pancreatic cancer. Molecular cancer. 2020; 19 (1): 1-17.
86. Zhang T, Li M, Lu H, Peng T. Up-regulation of circEIF6 contributes to pancreatic cancer development through targeting miR-557/SLC7A11/PI3K/AKT signaling. Cancer Management and Research. 2021; 13: 247.