Silencing NCAPD3 Inhibits Tumor Growth and Metastasis in Hepatocellular Carcinoma by Suppressing PI3K-AKT Signalling Pathway

Abstract

Objective

To evaluate the expression pattern of non-SMC condensin II complex subunit D3 (NCAPD3) in hepatocellular carcinoma (HCC) tissues, assess its association with clinical characteristics, and explore the effects of NCAPD3 on HCC cells and the potential underlying mechanisms.

Methods

NCAPD3expression in HCC tumors and adjacent noncancerous tissues was quantified via quantitative PCR. Patients were divided into high- and low-expression groups on the basis of NCAPD3levels, and associations with clinical parameters were assessed. The effects of NCAPD3 knockdown and the phosphatidylinositol-3-kinase (PI3K) agonist Y-P 740 on cell functions were examined via cell proliferation, Transwell migration, and invasion assays. Differentially expressed genes following NCAPD3knockdown in SMMC-7721 cells were identified via mRNA sequencing. Western blotting was performed to measure NCAPD3, AKT serine/threonine kinase 1 (AKT1), and phosphorylated AKT1 levels.

Results

NCAPD3 mRNA expression was notably upregulated in HCC tissues as compared with that in adjacent noncancer tissues. A positive correlation was observed between NCAPD3 expression and both lymphatic and distant metastases in patients with HCC. NCAPD3 knockdown reduced the proliferation and metastasis of SMMC-7721 and Huh-7 cells. mRNA sequencing revealed 140 downregulated genes and 125 upregulated genes. Further validation experiments confirmed that NCAPD3 modulated the PI3K-AKT signalling pathway and that the PI3K agonist Y-P 740 counteracted the effects of NCAPD3 knockdown.

Conclusions

Elevated NCAPD3 expression was strongly correlated with HCC metastasis. NCAPD3 inhibition impedes HCC cell growth and metastatic potential by suppressing the PI3K-AKT signalling pathway.

Keywords

Hepatocellular carcinoma / Non-SMC condensin II complex subunit D3 / PI3K-AKT signalling pathway / Oncogene

© The Author(s), under exclusive licence to Huazhong University of Science and Technology 2025

Author Contributions Jun Lv invovled in the study design. Jun Lv and Fu-yuan Gan performed main experiments and drafted the manuscript. Ming-hao Li and Qing-jun Yin analyzed results and made figures. Jun Lv revised the manuscript. All the authors have read and approved the final version of the manuscript.

Funding This project was supported by grants from Guangxi Nanning Qingxiu District Key Research and Development Program of Science and Technology Plan (no. 2020050), Guangxi Medical and Health Appropriate Technology Development, Promotion and Application Project (no. S2021097), Guangxi Key Research and Development Program (no. AB22080064), and Guangxi Natural Science Foundation (no. 2017GXNSFAA198126).

Data Availability Our manuscript has no associated data.

Declarations

Conflict of interest The authors declare that there is no conflict of interest with any financial organization or corporation or individual that can inappropriately influence this work.

Ethical approval and consent to participate The study on human tissues was approved by the Ethics Committee of the First Affiliated Hospital of the Guangxi Medical University. All patients understood the purpose of the study and provided written informed consent.

Human ethics The study on human tissues was approved by the Ethics Committee of the First Affiliated Hospital of the Guangxi Medical University.

Consent for publication Not applicable.

References

[1] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3):209-249.

[2] Rumgay H, Arnold M, Ferlay J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022; 77(6):1598-1606.

[3] Vogel A, Meyer T, Sapisochin G, et al. Hepatocellular carcinoma. Lancet. 2022; 400(10360):1345-1362.

[4] Feng F, Zhao Y. Hepatocellular carcinoma: Prevention, diagnosis, and treatment. Med Princ Pract. 2024; 33(5):414-423.

[5] Deutschman E, Ward JR, Kumar A, et al. Condensin II protein dysfunction impacts mitochondrial respiration and mitochondrial oxidative stress responses. J Cell Sci. 2019; 132(22):jcs233783.

[6] George CM, Bozler J, Nguyen HQ, et al. Condensins are required for maintenance of nuclear architecture. Cells. 2014; 3(3):865-882.

[7] Hartl TA, Sweeney SJ, Knepler PJ, et al. Condensin II resolves chromosomal associations to enable anaphase I segregation in drosophila male meiosis. PLoS Genet. 2008; 4(10):e1000228.

[8] Longworth MS, Herr A, Ji JY, et al. Rbf1 promotes chromatin condensation through a conserved interaction with the condensin ii protein dcap-d3. Genes Develop. 2008; 22(8):1011-1024.

[9] Yuan CW, Sun XL, Qiao LC, et al. Non-smc condensin i complex subunit d2 and non-smc condensin ii complex subunit d3-induces inflammation via the ikk/nf-κb pathway in ulcerative colitis. World J Gastroenterol. 2019; 25(47):6813-6822.

[10] Lapointe J, Malhotra S, Higgins JP, et al. HCAPD3 expression marks a prostate cancer subtype with favorable clinical behavior and androgen signaling signature. Am J Surg Pathol. 2008; 32(2):205-209.

[11] Jing Z, Liu Q, Xie W, et al. NCAPD3 promotes prostate cancer progression by up-regulating ezh2 and malat1 through stat3 and e2f1. Cell Signal. 2022; 92:110265.

[12] Zhang Y, Shao Y, Ren J, et al. Ncapd3 exerts tumor-promoting effects in prostatic cancer via dual impact on mir-30a-5p by stat3-malat1 and myc. Cell Death Discov. 2024; 10(1):159.

[13] Jing Z, Liu Q, He X, et al. NCAPD3 enhances warburg effect through c-myc and e2f1 and promotes the occurrence and progression of colorectal cancer. J Exp Clin Cancer Res. 2022; 41(1):198.

[14] Lu T, Yang J, Cai Y, et al. NCAPD3 promotes diffuse large b-cell lymphoma progression through modulating sirt1 expression in an h3k9 monomethylation-dependent manner. J Adv Res. 2024; S 2090-1232(24):00086-00089.

[15] Zhang SY, Luo Q, Xiao LR, et al. Role and mechanism of NCAPD3 in promoting malignant behaviors in gastric cancer. Front Pharmacol. 2024; 15:1341039.

[16] Yang F, Zheng Y, Luo Q, et al. Knockdown of NCAPD3 inhibits the tumorigenesis of non-small cell lung cancer by regulation of the pi3k/akt pathway. BMC Cancer. 2024; 24(1):408.

[17] Qu L, Che H, Zhao J, et al. NCAPD3 is a prognostic biomarker and is correlated with immune infiltrates in glioma. Histol Histopathol. 2024; 39(11):1473-1484.

[18] Moon H, Ro SW. MAPK/ERK signaling pathway in hepatocellular carcinoma. Cancers (Basel). 2021; 13(12):3026.

[19] Tian LY, Smit DJ, Jücker M. The role of PI3K/AKT/mTOR signaling in hepatocellular carcinoma metabolism. Int J Mol Sci. 2023; 24(3):2652.

[20] Hin Tang JJ, Hao Thng DK, Lim JJ, et al. JAK/STAT signaling in hepatocellular carcinoma. Hepatic Oncol. 2020; 7(1):Hep18.

[21] Wang Y, Deng B. Hepatocellular carcinoma: Molecular mechanism, targeted therapy, and biomarkers. Cancer Met Rev. 2023; 42(3):629-652.

[22] Jiří T, Igor K, Mba. Hepatocellular carcinoma future treatment options. Klin Onkol. 2020; 33(Supplementum 3):26-29.

[23] Kawano Y, Kaneya Y, Aoki Y, et al. Medical treatment for hepatocellular carcinoma in Japan. J Nippon Med Sch. 2022; 89(2):154-160.

[24] Galle PR, Dufour JF, Peck-Radosavljevic M, et al. Systemic therapy of advanced hepatocellular carcinoma. Future Oncol (London, England). 2021; 17(10):1237-1251.

[25] Sangro B, Sarobe P, Hervás-Stubbs S, et al. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021; 18(8):525-543.

[26] Wang X, Lu J. Immunotherapy for hepatocellular carcinoma. Chin Med J. 2024; 137(15):1765-1776.

[27] Ding J, Zhao W. The application of liquid biopsy techniques in high-risk population for hepatocellular carcinoma. Cancer Manag Res. 2022; 14:2735-2748.

[28] He Y, Sun MM, Zhang GG, et al. Targeting pi3k/akt signal transduction for cancer therapy. Signal Transd Target Ther. 2021; 6(1):425.

[29] Khezri MR, Jafari R, Yousefi K, et al. The PI3K/AKT signaling pathway in cancer: Molecular mechanisms and possible therapeutic interventions. Exp Mol Pathol. 2022; 127:104787.