PF4V1 affects the progression of oral squamous cell carcinoma by regulating Wnt/ β‑catenin pathway and angiogenesis

다국어 초록 (Multilingual Abstract)

Platelet factor-4 variant 1 (PF4V1) was recently described as a natural non-allelic gene variant of platelet factor-4 (PF4), which has been closely associated with the growth and metastasis of various cancers. Our previous research showed that PF4V1 was related to oral squamous cells carcinoma (OSCC) metastasis. Howerver, it is still not clear about the functional role of PF4V1 in OSCC. In this study, stably transfected cell lines were constructed and the expression level of PF4V1 was verified by real‐time polymerase chain reaction (RT-PCR) and western blot. The effect of PF4V1 on proliferation, migration, invasion, and apoptosis of oral cancer (OC) cells were detected. Moreover, a xenograft tumor model was constructed to evaluate the effect of PF4V1 on OSCC in vivo. Indicators of Wnt/β-catenin, angiogenesis and epithelial-mesenchymal transition (EMT) pathways were also examined. Stable cell lines with overexpression and inhibited expression of PF4V1 were constructed successfully. After stable transfection, PF4V1 significantly promoted the proliferation, migration, and invasion of OC cells in vitro, and their tumor formation in vivo. Furthermore, PF4V1 remarkably promoted the expression of β-catenin, VEGF, and FGF but suppressed the expression of GSK-3β. There was no statistically significant correlation between PF4V1 and EMT pathway. This study provides evidence that PF4V1 promotes the proliferation, migration, invasion and tumor formation of OC cells by regulating the Wnt/β-catenin pathway and angiogenesis. Our findings suggest that PF4V1 could be a very promising target of OSCC therapy in the future.

참고문헌 (Reference)

1 Wang SH, "beta-catenin deacetylation is essential for WNT-induced proliferation of breast cancer cells" 9 (9): 973-978, 2014

2 Krausova M, "Wnt signaling in adult intestinal stem cells and cancer" 26 (26): 570-579, 2014

3 Vandercappellen J, "The role of the CXC chemokines platelet factor-4 (PF4/PF-4) and its variant (PF4L1/PF-4var)in inflammation, angiogenesis and cancer" 22 (22): 1-18, 2011

4 Vandercappellen J, "The COOH-terminal peptide of platelet factor-4 variant (PF4L1/PF-4var(47-70)) strongly inhibits angiogenesis and suppresses B16 melanoma growth in vivo" 8 (8): 322-334, 2010

5 Ashihara E, "Targeting the canonical Wnt/beta-catenin pathway in hematological malignancies" 106 (106): 665-671, 2015

6 Vandercappellen J, "Stimulation of angiostatic platelet factor-4 variant (PF4L1/PF-4var) versus inhibition of angiogenic granulocyte chemotactic protein-2 (CXCL6/GCP-2) in normal and tumoral mesenchymal cells" 82 (82): 1519-1530, 2007

7 Li CP, "Potential markers from serum-purified exosomes for detecting oral squamous cell carcinoma metastasis" 28 (28): 1668-1681, 2019

8 Struyf S, "Platelets release PF4L1, a nonallelic variant of the chemokine platelet factor-4/PF4 and potent inhibitor of angiogenesis" 95 (95): 855-857, 2004

9 Struyf S, "Platelet factor-4 variant chemokine PF4L1 inhibits melanoma and lung carcinoma growth and metastasis by preventing angiogenesis" 67 (67): 5940-5948, 2007

10 Luo J, "PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/beta-catenin signaling pathway" 19 : 96-, 2019

11 Prats AC, "PF4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis" 89 : 25-33, 2013

12 Rosebush MS, "Oral cancer : enduring characteristics and emerging trends" 91 (91): 24-27, 2011

13 Rommelaere J, "Oncolytic parvoviruses as cancer therapeutics" 21 (21): 185-195, 2010

14 Breitbach CJ, "Navigating the clinical development landscape for oncolytic viruses and other cancer therapeutics: no shortcuts on the road to approval" 21 (21): 85-89, 2010

15 Wei D, "MicroRNA199a5p suppresses migration and invasion in oral squamous cell carcinoma through inhibiting the EMTrelated transcription factor SOX4" 44 (44): 185-195, 2019

16 Shi B, "MiR-106a directly targets LIMK1 to inhibit proliferation and EMT of oral carcinoma cells" 24 : 1-, 2019

17 Dai J, "Long non-coding RNA CRNDE regulates cell proliferation, migration, invasion, epithelial-mesenchymal transition and apoptosis in oral squamous cell carcinoma" 17 (17): 3330-3340, 2019

18 Lyu Q, "LncRNA MINCR activates Wnt/beta-catenin signals to promote cell proliferation and migration in oral squamous cell carcinoma" 215 (215): 924-930, 2019

19 Xian-Li T, "Higher expression of Linc00152 promotes bladder cancer proliferation and metastasis by activating the Wnt/β-catenin signaling pathway" 25 : 3221-3230, 2019

20 Warnakulasuriya S, "Global epidemiology of oral and oropharyngeal cancer" 45 (45): 309-316, 2009

21 Johnson LA, "Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen" 114 (114): 535-546, 2009

22 Negre O, "Gene therapy of the beta-hemoglobinopathies by lentiviral transfer of the beta(A(T87Q))-globin gene" 27 (27): 148-165, 2016

23 Dubrac A, "Functional divergence between 2 chemokines is conferred by single amino acid change" 116 (116): 4703-4711, 2010

24 Liu H, "FOXO3a modulates WNT/beta-catenin signaling and suppresses epithelialto-mesenchymal transition in prostate cancer cells" 27 (27): 510-518, 2015

25 Verbeke H, "Expression of angiostatic platelet factor-4var/PF4L1counterbalances angiogenic impulses of vascular endothelial growth factor, interleukin-8/CXCL8, and stromal cell-derived factor 1/CXCL12in esophageal and colorectal cancer" 41 (41): 990-1001, 2010

26 Acloque H, "Epithelial-mesenchymal transitions : the importance of changing cell state in development and disease" 119 (119): 1438-1449, 2009

27 Chen R, "Epidermal growth factor (EGF)autocrine activation of human platelets promotes EGF receptor–dependent oral squamous cell carcinoma invasion, migration, and epithelial mesenchymal transition" 201 (201): 2154-2164, 2018

28 Quemener C, "Dual roles for PF4 chemokines and CXCR3 in angiogenesis and invasion of pancreatic cancer" 76 (76): 6507-6519, 2016

29 Kumar SR, "Clinical development of gene therapy : results and lessons from recent successes" 3 : 16034-, 2016

30 Van Raemdonck K, "Angiostatic, tumor inflammatory and anti-tumor effects of PF4(47-70)and PF4L1(47-70)in an EGF-dependent breast cancer model" 5 (5): 10916-10933, 2014

31 Struyf S, "Angiostatic and chemotactic activities of the CXC chemokine PF4L1(platelet factor-4 variant)are mediated by CXCR3" 117 (117): 480-488, 2011