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2000
Volume 25, Issue 7
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Background

Osteosarcoma (OS) is a common malignancy among adolescents and children, characterized by a high propensity for metastasis and resistance to chemotherapy.

Aims

This study aimed to investigate the role of COL12A1, a gene often overexpressed in various cancers and associated with poor prognosis, in the progression of OS and explore the underlying mechanisms.

Methods

The expression pattern and potential function of COL12A1 in OS were evaluated using bioinformatics analyses, clinical sample examination, and OS cell lines. Various assays, including transwell, CCK-8, flow cytometry, and wound healing, were performed to assess the impact of COL12A1 on OS cell growth, cell cycle progression, apoptosis, invasion, and migration. Western blot analysis was conducted to investigate markers associated with the FAK/PI3K/AKT/mTOR pathway.

Results

COL12A1 expression was significantly elevated in OS tissues and cells. Upregulation of COL12A1 promoted cell growth, accelerated cell cycle progression, and enhanced migration and invasion while inhibiting apoptosis. Conversely, the knockdown of COL12A1 had the opposite effect. Additionally, COL12A1 over-expression increased the phosphorylation of components in the FAK/PI3K/AKT/mTOR pathway. The FAK inhibitor Y15 mitigated the effects of COL12A1 overexpression on cell apoptosis, invasion, proliferation, and the FAK/PI3K/AKT/mTOR pathway in OS.

Conclusion

Our findings indicated that COL12A1 enhanced OS development by activating the FAK/PI3K/AKT/mTOR pathway, suggesting that COL12A1 could serve as a valuable biomarker for the prediction and identification of OS patients.

© 2025 Bentham Science Publishers
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2025-10-26

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References

  1. GorlickR. KhannaC. Osteosarcoma.J. Bone Miner. Res.201025468369110.1002/jbmr.77 20205169
     [Google Scholar]
  2. YangM. ZhangY. LiuG. TIPE1 inhibits osteosarcoma tumorigenesis and progression by regulating PRMT1 mediated STAT3 arginine methylation.Cell Death Dis.202213981510.1038/s41419‑022‑05273‑y 36151091
     [Google Scholar]
  3. WangG. ZhangM. MengP. Anticarin-β shows a promising anti-osteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis.Acta Pharm. Sin. B20221252268227910.1016/j.apsb.2021.12.024 35646538
     [Google Scholar]
  4. CuiJ. DeanD. HornicekF.J. ChenZ. DuanZ. The role of extracelluar matrix in osteosarcoma progression and metastasis.J. Exp. Clin. Cancer Res.202039117810.1186/s13046‑020‑01685‑w 32887645
     [Google Scholar]
  5. de AzevedoJ.W.V. de Medeiros FernandesT.A.A. FernandesJ.V.Jr Biology and pathogenesis of human osteosarcoma.Oncol. Lett.202019210991116 31966039
     [Google Scholar]
  6. XiaoH. JensenP.E. ChenX. Elimination of osteosarcoma by necroptosis with graphene oxide-associated Anti-HER2 antibodies.Int. J. Mol. Sci.20192018436010.3390/ijms20184360 31491952
     [Google Scholar]
  7. TanJ. YangB. ZhongH. Circular RNA circEMB promotes osteosarcoma progression and metastasis by sponging miR-3184-5p and regulating EGFR expression.Biomark. Res.2023111310.1186/s40364‑022‑00442‑9 36611218
     [Google Scholar]
  8. GasparN. OcceanB.V. PacquementH. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study.Eur. J. Cancer201888576610.1016/j.ejca.2017.09.036 29190507
     [Google Scholar]
  9. LiY. HouH. ZhangP. ZhangZ. Co-delivery of doxorubicin and paclitaxel by reduction/pH dual responsive nanocarriers for osteosarcoma therapy.Drug Deliv.20202711044105310.1080/10717544.2020.1785049 32633576
     [Google Scholar]
  10. LeeC.W. HuangC.C.Y. ChiM.C. Naringenin induces ROS-mediated ER stress, autophagy, and apoptosis in human osteosarcoma cell lines.Molecules202227237310.3390/molecules27020373 35056691
     [Google Scholar]
  11. WangX. ZhouT. YangX. DDRGK1 enhances osteosarcoma chemoresistance via inhibiting KEAP1‐mediated NRF2 ubiquitination.Adv. Sci. (Weinh.)20231014220443810.1002/advs.202204438 36965071
     [Google Scholar]
  12. ZhouC. ZhangZ. ZhuX. N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1.EBioMedicine20205910295510.1016/j.ebiom.2020.102955 32853985
     [Google Scholar]
  13. DongS. HuoH. MaoY. LiX. DongL. A risk score model for the prediction of osteosarcoma metastasis.FEBS Open Bio20199351952610.1002/2211‑5463.12592 30868060
     [Google Scholar]
  14. LuetkeA. MeyersP.A. LewisI. JuergensH. Osteosarcoma treatment – Where do we stand? A state of the art review.Cancer Treat. Rev.201440452353210.1016/j.ctrv.2013.11.006 24345772
     [Google Scholar]
  15. QinT. ZhuW. KanX. LiL. WuD. Luteolin attenuates the chemoresistance of osteosarcoma through inhibiting the PTN/β-catenin/MDR1 signaling axis by upregulating miR-384.J. Bone Oncol.20223410042910.1016/j.jbo.2022.100429 35493691
     [Google Scholar]
  16. ShaoX. XiangS. ChenY. Inhibition of M2-like macrophages by all-trans retinoic acid prevents cancer initiation and stemness in osteosarcoma cells.Acta Pharmacol. Sin.201940101343135010.1038/s41401‑019‑0262‑4 31296953
     [Google Scholar]
  17. QiX. LiY. ZhangY. KLF4 functions as an oncogene in promoting cancer stem cell-like characteristics in osteosarcoma cells.Acta Pharmacol. Sin.201940454655510.1038/s41401‑018‑0050‑6 29930276
     [Google Scholar]
  18. GereckeD.R. OlsonP.F. KochM. Complete primary structure of two splice variants of collagen XII, and assignment of alpha 1(XII) collagen (COL12A1), alpha 1(IX) collagen (COL9A1), and alpha 1(XIX) collagen (COL19A1) to human chromosome 6q12-q13.Genomics199741223624210.1006/geno.1997.4638 9143499
     [Google Scholar]
  19. GinevičienėV. UrnikytėA. Association of COL12A1 rs970547 polymorphism with elite athlete status.Biomedicines20221010249510.3390/biomedicines10102495 36289757
     [Google Scholar]
  20. PosthumusM. SeptemberA.V. O’CuinneagainD. van der MerweW. SchwellnusM.P. CollinsM. The association between the COL12A1 gene and anterior cruciate ligament ruptures.Br. J. Sports Med.201044161160116510.1136/bjsm.2009.060756 19443461
     [Google Scholar]
  21. HicksD. FarsaniG.T. LavalS. Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy.Hum. Mol. Genet.20142392353236310.1093/hmg/ddt637 24334769
     [Google Scholar]
  22. Jezela-StanekA. WalczakA. ŁaźniewskiM. Novel COL12A1 variant as a cause of mild familial extracellular matrix‐related myopathy.Clin. Genet.201995673673810.1111/cge.13534 30920656
     [Google Scholar]
  23. ZhaoH. LjungbergB. GrankvistK. RasmusonT. TibshiraniR. BrooksJ.D. Gene expression profiling predicts survival in conventional renal cell carcinoma.PLoS Med.200531e1310.1371/journal.pmed.0030013 16318415
     [Google Scholar]
  24. JanuchowskiR. ŚwierczewskaM. SterzyńskaK. WojtowiczK. NowickiM. ZabelM. Increased expression of several collagen genes is associated with drug resistance in ovarian cancer cell lines.J. Cancer20167101295131010.7150/jca.15371 27390605
     [Google Scholar]
  25. TorresS. BartoloméR.A. MendesM. Proteome profiling of cancer-associated fibroblasts identifies novel proinflammatory signatures and prognostic markers for colorectal cancer.Clin. Cancer Res.201319216006601910.1158/1078‑0432.CCR‑13‑1130 24025712
     [Google Scholar]
  26. LiT. FuJ. ZengZ. TIMER2.0 for analysis of tumor-infiltrating immune cells.Nucleic Acids Res.202048W1W509-1410.1093/nar/gkaa407 32442275
     [Google Scholar]
  27. StaehlkeS. ReblH. NebeB. Phenotypic stability of the human MG‐63 osteoblastic cell line at different passages.Cell Biol. Int.2019431223210.1002/cbin.11073 30444078
     [Google Scholar]
  28. ChauhanR. GuptaA. MalhotraL. Ubiquitin specific peptidase 37 and PCNA interaction promotes osteosarcoma pathogenesis by modulating replication fork progression.J. Transl. Med.202321128610.1186/s12967‑023‑04126‑2 37118828
     [Google Scholar]
  29. HsuC.T. HuangY.F. HsiehC.P. WuC.C. ShenT.S. JNK inactivation induces polyploidy and drug-resistance in coronarin d-treated osteosarcoma cells.Molecules2018239212110.3390/molecules23092121 30142914
     [Google Scholar]
  30. HeJ ChenC ChenL Honeycomb-like hydrogel microspheres for 3D bulk construction of tumor models. research 2022;20222022/980976310.34133/2022/980976335233536
     [Google Scholar]
  31. GuQ. LuoY. ChenC. JiangD. HuangQ. WangX. GREM1 overexpression inhibits proliferation, migration and angiogenesis of osteosarcoma.Exp. Cell Res.2019384111161910.1016/j.yexcr.2019.111619 31525341
     [Google Scholar]
  32. SadykovaL.R. NtekimA.I. Muyangwa-SemenovaM. Epidemiology and risk factors of osteosarcoma.Cancer Invest.202038525926910.1080/07357907.2020.1768401 32400205
     [Google Scholar]
  33. YangM. YanM. ZhangR. LiJ. LuoZ. Side population cells isolated from human osteosarcoma are enriched with tumor‐initiating cells.Cancer Sci.2011102101774178110.1111/j.1349‑7006.2011.02028.x 21740477
     [Google Scholar]
  34. ZhouZ. LiY. KuangM. The CD24+ cell subset promotes invasion and metastasis in human osteosarcoma.EBioMedicine20205110259810.1016/j.ebiom.2019.102598 31901872
     [Google Scholar]
  35. DuM.D. HeK.Y. QinG. ChenJ. LiJ.Y. Adriamycin resistance-associated prohibitin gene inhibits proliferation of human osteosarcoma MG63 cells by interacting with oncogenes and tumor suppressor genes.Oncol. Lett.20161231994200010.3892/ol.2016.4862 27602127
     [Google Scholar]
  36. WuF. XuJ. JinM. Development and verification of a hypoxic gene signature for predicting prognosis, immune microenvironment, and chemosensitivity for osteosarcoma.Front. Mol. Biosci.2022870514810.3389/fmolb.2021.705148 35071320
     [Google Scholar]
  37. HuX.K. RaoS.S. TanY.J. Fructose-coated Angstrom silver inhibits osteosarcoma growth and metastasis via promoting ROS-dependent apoptosis through the alteration of glucose metabolism by inhibiting PDK.Theranostics202010177710772910.7150/thno.45858 32685015
     [Google Scholar]
  38. ZhangH.J. YangJ.J. LuJ.P. Use of intra-arterial chemotherapy and embolization before limb salvage surgery for osteosarcoma of the lower extremity.Cardiovasc. Intervent. Radiol.200932467267810.1007/s00270‑009‑9546‑2 19296158
     [Google Scholar]
  39. DawN.C. ChouA.J. JaffeN. Recurrent osteosarcoma with a single pulmonary metastasis: A multi-institutional review.Br. J. Cancer2015112227828210.1038/bjc.2014.585 25422914
     [Google Scholar]
  40. LiD. TojiS. WatanabeK. TorigoeT. TsukaharaT. Identification of novel human leukocyte antigen‐A*11:01‐restricted cytotoxic T‐lymphocyte epitopes derived from osteosarcoma antigen papillomavirus binding factor.Cancer Sci.201911041156116810.1111/cas.13973 30767336
     [Google Scholar]
  41. YuW.X. TangL.N. LinF. YaoY. ShenZ. Comparison of pemetrexed plus cisplatin with gemcitabine plus docetaxel in refractory/metastatic osteosarcoma: Clinical outcomes from a retrospective database monitored in a single institute.Oncol. Lett.2014852243224810.3892/ol.2014.2472 25289103
     [Google Scholar]
  42. KeremuA. AiniA. MaimaitirexiatiY. Overcoming cisplatin resistance in osteosarcoma through the miR-199a -modulated inhibition of HIF-1α.Biosci. Rep.20193911BSR2017008010.1042/BSR20170080 28442599
     [Google Scholar]
  43. JiangX. WuM. XuX. COL12A1, a novel potential prognostic factor and therapeutic target in gastric cancer.Mol. Med. Rep.20192043103311210.3892/mmr.2019.10548 31432110
     [Google Scholar]
  44. LiC. JinW. ZhangD. TianS. Clinical significance of microRNA-1180-3p for colorectal cancer and effect of its alteration on cell function.Bioengineered2021122104911050010.1080/21655979.2021.1997694 34723759
     [Google Scholar]
  45. LiJ. LiZ. XuY. HuangC. ShanB. METTL3 facilitates tumor progression by COL12A1/MAPK signaling pathway in esophageal squamous cell carcinoma.J. Cancer20221361972198410.7150/jca.66830 35399719
     [Google Scholar]
  46. VergheseE.T. DruryR. GreenC.A. MiR-26b is down-regulated in carcinoma-associated fibroblasts from ER-positive breast cancers leading to enhanced cell migration and invasion.J. Pathol.2013231338839910.1002/path.4248 23939832
     [Google Scholar]
  47. YanY. LiangQ. LiuY. ZhouS. XuZ. COL12A1 as a prognostic biomarker links immunotherapy response in breast cancer.Endocr. Relat. Cancer2023305e23001210.1530/ERC‑23‑0012 36877531
     [Google Scholar]
  48. LiY. SuZ. WeiB. QinM. LiangZ. Bioinformatics analysis identified MMP14 and COL12A1 as immune-related biomarkers associated with pancreatic adenocarcinoma prognosis.Math. Biosci. Eng.20211855921594210.3934/mbe.2021296 34517516
     [Google Scholar]
  49. SulzmaierF.J. JeanC. SchlaepferD.D. FAK in cancer: Mechanistic findings and clinical applications.Nat. Rev. Cancer201414959861010.1038/nrc3792 25098269
     [Google Scholar]
  50. KiwanukaE. LeeC.C.Y. HacklF. Cdc42 and p190RhoGAP activation by CCN2 regulates cell spreading and polarity and induces actin disassembly in migrating keratinocytes.Int. Wound J.201613337238110.1111/iwj.12315 25185742
     [Google Scholar]
  51. ThomS.R. BhopaleV.M. MilovanovaT.N. YangM. BogushM. BuerkD.G. Nitric-oxide synthase-2 linkage to focal adhesion kinase in neutrophils influences enzyme activity and β2 integrin function.J. Biol. Chem.201328874810481810.1074/jbc.M112.426353 23297409
     [Google Scholar]
  52. LukC.T. ShiS.Y. CaiE.P. FAK signalling controls insulin sensitivity through regulation of adipocyte survival.Nat. Commun.2017811436010.1038/ncomms14360 28165007
     [Google Scholar]
  53. JanevA. RamutaT.Ž. JermanU.D. Human amniotic membrane inhibits migration and invasion of muscle-invasive bladder cancer urothelial cells by downregulating the FAK/PI3K/Akt/mTOR signalling pathway.Sci. Rep.20231311922710.1038/s41598‑023‑46091‑2 37932474
     [Google Scholar]
  54. HaoH.F. NaomotoY. BaoX.H. Progress in researches about focal adhesion kinase ingastrointestinal tract.World J. Gastroenterol.200915475916592310.3748/wjg.15.5916 20014455
     [Google Scholar]
  55. FlaminiM.I. UzairI.D. PennacchioG.E. Thyroid hormone controls breast cancer cell movement via integrin αV/β3/SRC/FAK/PI3-kinases.Horm. Cancer201781162710.1007/s12672‑016‑0280‑3 28050799
     [Google Scholar]
  56. LiuX. GaoY. LongX. Type I collagen promotes the migration and myogenic differentiation of C2C12 myoblasts via the release of interleukin-6 mediated by FAK/NF-κB p65 activation.Food Funct.202011132833810.1039/C9FO01346F 31799535
     [Google Scholar]
  57. LiW. WangH. ZhangJ. ZhaiL. ChenW. ZhaoC. miR‐199a‐5p regulates β1 integrin through Ets‐1 to suppress invasion in breast cancer.Cancer Sci.2016107791692310.1111/cas.12952 27094578
     [Google Scholar]
  58. WangY. MaX. XuE. Identifying squalene epoxidase as a metabolic vulnerability in high‐risk osteosarcoma using an artificial intelligence‐derived prognostic index.Clin. Transl. Med.2024142e158610.1002/ctm2.1586 38372422
     [Google Scholar]
  59. NepstadI. ReikvamH. BrennerA. BruserudØ. HatfieldK. Resistance to the antiproliferative in vitro effect of PI3K-Akt-mTOR inhibition in primary human acute myeloid leukemia cells is associated with altered cell metabolism.Int. J. Mol. Sci.201819238210.3390/ijms19020382 29382066
     [Google Scholar]
  60. ChenK. JiaoJ. XueJ. Ginsenoside CK induces apoptosis and suppresses proliferation and invasion of human osteosarcoma cells through the PI3K/mTOR/p70S6K1 pathway.Oncol. Rep.202043388689610.3892/or.2020.7460 32020217
     [Google Scholar]
  61. ZhangY. YangF. Analyzing the disease module associated with osteosarcoma via a network and pathway based approach.Exp. Ther. Med.20181632584259210.3892/etm.2018.6506 30210606
     [Google Scholar]
  62. QiX. ChenY. LiuS. Sanguinarine inhibits melanoma invasion and migration by targeting the FAK/PI3K/AKT/mTOR signalling pathway.Pharm. Biol.202361169670910.1080/13880209.2023.2200787 37092313
     [Google Scholar]
  63. ShanthiE. KrishnaM.H. AruneshG.M. Venkateswara ReddyK. Sooriya KumarJ. ViswanadhanV.N. Focal adhesion kinase inhibitors in the treatment of metastatic cancer: A patent review.Expert Opin. Ther. Pat.201424101077110010.1517/13543776.2014.948845 25113248
     [Google Scholar]
  64. WangS.E. XiangB. ZentR. QuarantaV. PozziA. ArteagaC.L. Transforming growth factor beta induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton.Cancer Res.200969247548210.1158/0008‑5472.CAN‑08‑2649 19147560
     [Google Scholar]
  65. LeeD.S. KimJ.E. P2 × 7 receptor inhibits astroglial autophagy via regulating FAK- and PHLPP1/2-mediated AKT-S473 phosphorylation following kainic acid-induced seizures.Int. J. Mol. Sci.20202118647610.3390/ijms21186476 32899862
     [Google Scholar]
  66. JiangK. XuL. NingJ. ChengF. FAP promotes clear cell renal cell carcinoma progression via activating the PI3K/AKT/mTOR signaling pathway.Cancer Cell Int.202323121710.1186/s12935‑023‑03073‑8 37752545
     [Google Scholar]
  67. YuanR. FanQ. LiangX. Cucurbitacin B inhibits TGF-β1-induced epithelial–mesenchymal transition (EMT) in NSCLC through regulating ROS and PI3K/Akt/mTOR pathways.Chin. Med.20221712410.1186/s13020‑022‑00581‑z 35183200
     [Google Scholar]
  68. HuangJ. LiJ. TangJ. ZDHHC22-mediated mTOR palmitoylation restrains breast cancer growth and endocrine therapy resistance.Int. J. Biol. Sci.20221872833285010.7150/ijbs.70544 35541896
     [Google Scholar]
  69. ArnoldD. SeufferleinT. Targeted treatments in colorectal cancer: State of the art and future perspectives.Gut201059683885810.1136/gut.2009.196006 20551469
     [Google Scholar]
  70. HuangJ. LiuC. DuanS. Gigantol inhibits proliferation and enhances DDP-induced apoptosis in breast-cancer cells by downregulating the PI3K/Akt/mTOR signaling pathway.Life Sci.202127411935410.1016/j.lfs.2021.119354 33737087
     [Google Scholar]
/content/journals/cmm/10.2174/0115665240322280240903111159
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COL12A1 Promotes Osteosarcoma Progression via the FAK/PI3K/AKT/mTOR Pathway
Current Molecular Medicine 25, 902 (2025); https://doi.org/10.2174/0115665240322280240903111159
/content/journals/cmm/10.2174/0115665240322280240903111159
/content/journals/cmm/10.2174/0115665240322280240903111159
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  • Article Type:     Research Article
Keyword(s): chemotherapy; COL12A1; FAK/PI3K/AKT/mTOR signaling; metastasis; Osteosarcoma; therapeutic target

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