PAMR1 regulates hepatocellular carcinoma cell proliferation and migration and affects patient prognosis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Tianyuan , LI Jie , ZHOU Bo ,  CHEN Ping

Department of Hepatobiliary Surgery, Arm Characteristic Medical Center, Army Medical University, Chongqing 400042, P. R. China;

Corresponding author：

CHEN Ping, Email: chenping@tmmu.edu.cn

Keywords：

hepatocellular carcinoma; peptidase domain containing associated with muscle regeneration 1; bioinformatics; cell proliferation; cell migration

DOI：

10.7507/1007-9424.202504149

Video：

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Objective To investigate the role of Peptidase domain containing associated with muscle regeneration 1 (PAMR1) in the proliferation, migration, and prognosis of hepatocellular carcinoma (HCC) through cellular experiments and clinical sample validation. Methods ① Bioinformatics analysis was performed on datasets from the GEO public database to identify and screen for key genes, ultimately selecting PAMR1 for further study. Findings were validated using data from the TCGA database and six primary HCC surgical specimens obtained from the Army Characteristic Medical Center of Army Medical University between February 2024 to June 2024.② PAMR1-overexpressing cell lines were established using HCC cell lines Huh7 and Lm3. Cells were transfected with either the recombinant plasmid pcDNA3.1(+)-PAMR1 (overexpression group, OE) or the empty vector pcDNA3.1(+) (negative control group, NC), with n=5 per group. The effects of PAMR1 on HCC cell proliferation and migration were assessed using the Cell Counting Kit-8 (CCK-8) assay and wound healing assay, respectively.③ Pathological specimens and clinical data were collected from 61 patients with primary HCC who underwent surgical resection at the Army Characteristic Medical Center of Army Medical University between May 2019 and April 2020. The impact of PAMR1 expression on disease-free survival (DFS) was evaluated. Results ① PAMR1 was identified as a candidate gene through GEO database screening and was found to be downregulated in HCC tissues based on both TCGA data and the six local surgical specimens.② The CCK-8 assay revealed that cell proliferation was significantly inhibited in the PAMR1 overexpression group compared to the negative control group (P < 0.05). Similarly, the wound healing assay demonstrated reduced migratory capability in PAMR1-overexpressing cells (P < 0.05).③ Multivariate Cox proportional hazards regression analysis of patient data indicated that high PAMR1 expression serves as an independent protective factor for prognosis in HCC (HR = 0.335, P < 0.05). Conclusion PAMR1 serves as a crucial gene in hepatocellular carcinoma, significantly suppressing tumor cell proliferation and migration while functioning as a protective factor that positively influences patient prognosis.

1.	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2.	姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
3.	Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers, 2021, 7(1): 6.
4.	Choi JH, Thung SN. Advances in histological and molecular classification of hepatocellular carcinoma. Biomedicines, 2023, 11(9): 2582. doi: 10.3390/biomedicines11092582.
5.	徐若翔, 曾智明, 朱广志, 等. 肝细胞癌AASLD(2023年版)、NCCN(2024年版)、ASCO(2024年版)指南和中国《原发性肝癌诊疗指南(2024年版)》更新解读, 中国普外基础与临床杂志, 2025, 32(2): 184-191.
6.	赵磊. 肝细胞癌的新辅助治疗: 现状与展望. 中国普通外科杂志, 2025, 34(7): 1347-1352.
7.	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.
8.	Václav T. Surgical treatment of hepatocellular carcinoma. Klin Onkol, 2020 Fall, 33(Supplementum 3): 30-33.
9.	Hsieh CL, Peng CM, Chen CW, et al. Benefits and drawbacks of radiofrequency ablation via percutaneous or minimally invasive surgery for treating hepatocellular carcinoma. World J Gastrointest Surg, 2024, 16(11): 3400-3407.
10.	Kulkarni AV, Singal AG, Reddy KR. Review article: liver transplantation for hepatocellular carcinoma in the era of immune checkpoint inhibitors. Aliment Pharmacol Ther, 2025, 62(6): 585-601.
11.	Takamoto T, Nara S, Ban D, et al. Chronological evolution in liver resection for hepatocellular carcinoma: Prognostic trends across three decades in early to advanced stages. Eur J Surg Oncol, 2025, 51(2): 109461. doi: 10.1016/j.ejso.2024.109461.
12.	Abdelhamed W, El-Kassas M. Hepatocellular carcinoma recurrence: predictors and management. Liver Res, 2023, 7(4): 321-332.
13.	Krupa K, Fudalej M, Cencelewicz-Lesikow A, et al. Current treatment methods in hepatocellular carcinoma. Cancers (Basel), 2024, 16(23): 4059. doi: 10.3390/cancers16234059.
14.	蓝晨露, 曾智明, 朱广志, 等. 肝细胞癌转化治疗研究进展. 中国普外基础与临床杂志, 2024, 31(12): 1424-1429.
15.	Pinter M, Scheiner B, Pinato DJ. Immune checkpoint inhibitors in hepatocellular carcinoma: emerging challenges in clinical practice. Lancet Gastroenterol Hepatol, 2023, 8(8): 760-770.
16.	Xing R, Gao J, Cui Q, et al. Strategies to Improve the Antitumor Effect of Immunotherapy for Hepatocellular Carcinoma. Front Immunol, 2021, 12: 783236. doi: 10.3389/fimmu.2021.783236.
17.	Szilveszter RM, Muntean M, Florea A. Molecular mechanisms in tumorigenesis of hepatocellular carcinoma and in target treatments-an overview. Biomolecules, 2024, 14(6): 656. doi: 10.3390/biom14060656.
18.	Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol, 2023, 29(6): 1054-1075.
19.	Peng Z, Fan W, Zhu B, et al. Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: a phase Ⅲ, randomized clinical trial (LAUNCH). J Clin Oncol, 2023, 41(1): 117-127.
20.	Lo PH, Tanikawa C, Katagiri T, et al. Identification of novel epigenetically inactivated gene PAMR1 in breast carcinoma. Oncol Rep, 2015, 33(1): 267-273.
21.	Yang R, Ma M, Yu S, et al. High expression of PAMR1 predicts favorable prognosis and inhibits proliferation, invasion, and migration in cervical cancer. Front Oncol, 2021, 11: 742017. doi: 10.3389/fonc.2021.742017.
22.	卢英, 雍景超, 吴志奇. 甲胎蛋白阴性肝细胞癌患者的预后分析. 南京医科大学学报(自然科学版), 2023, 43(11): 1527-1534.
23.	Nakayama Y, Nara N, Kawakita Y, et al. Cloning of cDNA encoding a regeneration-associated muscle protease whose expression is attenuated in cell lines derived from Duchenne muscular dystrophy patients. Am J Pathol, 2004, 164(5): 1773-1782.
24.	Punjabi LS, Goh CHR, Sittampalam K. Expanding the spectrum of GLI1-altered mesenchymal tumors-a high-grade uterine sarcoma harboring a novel PAMR1: : GLI1 fusion and literature review of GLI1-altered mesenchymal neoplasms of the gynecologic tract. Genes Chromosomes Cancer, 2023, 62(2): 107-114.
25.	Sun J, Zhang Z, Cai J, et al. Identification of hub genes in liver hepatocellular carcinoma based on weighted gene co-expression network analysis. Biochem Genet, 2025, 63(3): 2120-2139.
26.	Wang S, Zhu M, Wang Q, et al. Alpha-fetoprotein inhibits autophagy to promote malignant behaviour in hepatocellular carcinoma cells by activating PI3K/AKT/mTOR signalling. Cell Death & Disease, 2018, 9(10): 1027. doi: 10.1038/s41419-018-1036-5.
27.	Zheng L, Gong W, Liang P, et al. Effects of AFP-activated PI3K/Akt signaling pathway on cell proliferation of liver cancer. Tumour Biol, 2014, 35(5): 4095-4099.
28.	Cheng CJ, Lin YC, Tsai MT, et al. SCUBE2 suppresses breast tumor cell proliferation and confers a favorable prognosis in invasive breast cancer. Cancer Res, 2009, 69(8): 3634-3641.
29.	Lin YC, Chen CC, Cheng CJ, et al. Domain and functional analysis of a novel breast tumor suppressor protein, SCUBE2. J Biol Chem, 2011, 286(30): 27039-27047.
30.	Lin YC, Lee YC, Li LH, et al. Tumor suppressor SCUBE2 inhibits breast-cancer cell migration and invasion through the reversal of epithelial-mesenchymal transition. J Cell Sci, 2014, 127(Pt 1): 85-100.
31.	Massimi M, Ragusa F, Cardarelli S, et al. Targeting cyclic AMP signalling in hepatocellular carcinoma. Cells, 2019, 8(12): 1511. doi: 10.3390/cells8121511.
32.	Yu H, Wu X, Liu Y, et al. Single-gene mutations in hepatocellular carcinoma: applications and challenges in precision medicine. Int J Med Sci, 2025, 22(13): 3268-3276.
33.	Liu M, Wen Y. Point-of-care testing for early-stage liver cancer diagnosis and personalized medicine: Biomarkers, current technologies and perspectives. Heliyon, 2024, 10(19): e38444. doi: 10.1016/j.heliyon.2024.e38444.
34.	Wang F, Breslin S J P, Qiu W. Novel oncogenes and tumor suppressor genes in hepatocellular carcinoma. Liver Res, 2021, 5(4): 195-203.
35.	Li J, Bai L, Xin Z, et al. TERT-TP53 mutations: a novel biomarker pair for hepatocellular carcinoma recurrence and prognosis. Sci Rep, 2025, 15(1): 3620. doi: 10.1038/s41598-025-87545-z.
36.	Qiao Y, Wang J, Karagoz E, et al. Axis inhibition protein 1 (Axin1) deletion-induced hepatocarcinogenesis requires intact β-catenin but not Notch cascade in mice. Hepatology, 2019, 70(6): 2003-2017.
37.	Xu C, Xu Z, Zhang Y, et al. β-Catenin signaling in hepatocellular carcinoma. J Clin Invest, 2022, 132(4): e154515. doi: 10.1172/JCI154515.
38.	Yan B, Peng Z, Xing C. SORBS2, mediated by MEF2D, suppresses the metastasis of human hepatocellular carcinoma by inhibitiing the c-Abl-ERK signaling pathway. Am J Cancer Res, 2019, 9(12): 2706-2718.
39.	Rahimi-Farsi N, Bostanian F, Shahbazi T, et al. Novel oncogenes and tumor suppressor genes in Hepatocellular Carcinoma: Carcinogenesis, progression, and therapeutic targets. Gene, 2025, 941: 149229. doi: 10.1016/j.gene.2025.149229.
40.	Khorkova O, Stahl J, Joji A, et al. Amplifying gene expression with RNA-targeted therapeutics. Nat Rev Drug Discov, 2023, 22(7): 539-561.

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. 姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
3. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers, 2021, 7(1): 6.
4. Choi JH, Thung SN. Advances in histological and molecular classification of hepatocellular carcinoma. Biomedicines, 2023, 11(9): 2582. doi: 10.3390/biomedicines11092582.
5. 徐若翔, 曾智明, 朱广志, 等. 肝细胞癌AASLD(2023年版)、NCCN(2024年版)、ASCO(2024年版)指南和中国《原发性肝癌诊疗指南(2024年版)》更新解读, 中国普外基础与临床杂志, 2025, 32(2): 184-191.
6. 赵磊. 肝细胞癌的新辅助治疗: 现状与展望. 中国普通外科杂志, 2025, 34(7): 1347-1352.
7. 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.
8. Václav T. Surgical treatment of hepatocellular carcinoma. Klin Onkol, 2020 Fall, 33(Supplementum 3): 30-33.
9. Hsieh CL, Peng CM, Chen CW, et al. Benefits and drawbacks of radiofrequency ablation via percutaneous or minimally invasive surgery for treating hepatocellular carcinoma. World J Gastrointest Surg, 2024, 16(11): 3400-3407.
10. Kulkarni AV, Singal AG, Reddy KR. Review article: liver transplantation for hepatocellular carcinoma in the era of immune checkpoint inhibitors. Aliment Pharmacol Ther, 2025, 62(6): 585-601.
11. Takamoto T, Nara S, Ban D, et al. Chronological evolution in liver resection for hepatocellular carcinoma: Prognostic trends across three decades in early to advanced stages. Eur J Surg Oncol, 2025, 51(2): 109461. doi: 10.1016/j.ejso.2024.109461.
12. Abdelhamed W, El-Kassas M. Hepatocellular carcinoma recurrence: predictors and management. Liver Res, 2023, 7(4): 321-332.
13. Krupa K, Fudalej M, Cencelewicz-Lesikow A, et al. Current treatment methods in hepatocellular carcinoma. Cancers (Basel), 2024, 16(23): 4059. doi: 10.3390/cancers16234059.
14. 蓝晨露, 曾智明, 朱广志, 等. 肝细胞癌转化治疗研究进展. 中国普外基础与临床杂志, 2024, 31(12): 1424-1429.
15. Pinter M, Scheiner B, Pinato DJ. Immune checkpoint inhibitors in hepatocellular carcinoma: emerging challenges in clinical practice. Lancet Gastroenterol Hepatol, 2023, 8(8): 760-770.
16. Xing R, Gao J, Cui Q, et al. Strategies to Improve the Antitumor Effect of Immunotherapy for Hepatocellular Carcinoma. Front Immunol, 2021, 12: 783236. doi: 10.3389/fimmu.2021.783236.
17. Szilveszter RM, Muntean M, Florea A. Molecular mechanisms in tumorigenesis of hepatocellular carcinoma and in target treatments-an overview. Biomolecules, 2024, 14(6): 656. doi: 10.3390/biom14060656.
18. Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol, 2023, 29(6): 1054-1075.
19. Peng Z, Fan W, Zhu B, et al. Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: a phase Ⅲ, randomized clinical trial (LAUNCH). J Clin Oncol, 2023, 41(1): 117-127.
20. Lo PH, Tanikawa C, Katagiri T, et al. Identification of novel epigenetically inactivated gene PAMR1 in breast carcinoma. Oncol Rep, 2015, 33(1): 267-273.
21. Yang R, Ma M, Yu S, et al. High expression of PAMR1 predicts favorable prognosis and inhibits proliferation, invasion, and migration in cervical cancer. Front Oncol, 2021, 11: 742017. doi: 10.3389/fonc.2021.742017.
22. 卢英, 雍景超, 吴志奇. 甲胎蛋白阴性肝细胞癌患者的预后分析. 南京医科大学学报(自然科学版), 2023, 43(11): 1527-1534.
23. Nakayama Y, Nara N, Kawakita Y, et al. Cloning of cDNA encoding a regeneration-associated muscle protease whose expression is attenuated in cell lines derived from Duchenne muscular dystrophy patients. Am J Pathol, 2004, 164(5): 1773-1782.
24. Punjabi LS, Goh CHR, Sittampalam K. Expanding the spectrum of GLI1-altered mesenchymal tumors-a high-grade uterine sarcoma harboring a novel PAMR1: : GLI1 fusion and literature review of GLI1-altered mesenchymal neoplasms of the gynecologic tract. Genes Chromosomes Cancer, 2023, 62(2): 107-114.
25. Sun J, Zhang Z, Cai J, et al. Identification of hub genes in liver hepatocellular carcinoma based on weighted gene co-expression network analysis. Biochem Genet, 2025, 63(3): 2120-2139.
26. Wang S, Zhu M, Wang Q, et al. Alpha-fetoprotein inhibits autophagy to promote malignant behaviour in hepatocellular carcinoma cells by activating PI3K/AKT/mTOR signalling. Cell Death & Disease, 2018, 9(10): 1027. doi: 10.1038/s41419-018-1036-5.
27. Zheng L, Gong W, Liang P, et al. Effects of AFP-activated PI3K/Akt signaling pathway on cell proliferation of liver cancer. Tumour Biol, 2014, 35(5): 4095-4099.
28. Cheng CJ, Lin YC, Tsai MT, et al. SCUBE2 suppresses breast tumor cell proliferation and confers a favorable prognosis in invasive breast cancer. Cancer Res, 2009, 69(8): 3634-3641.
29. Lin YC, Chen CC, Cheng CJ, et al. Domain and functional analysis of a novel breast tumor suppressor protein, SCUBE2. J Biol Chem, 2011, 286(30): 27039-27047.
30. Lin YC, Lee YC, Li LH, et al. Tumor suppressor SCUBE2 inhibits breast-cancer cell migration and invasion through the reversal of epithelial-mesenchymal transition. J Cell Sci, 2014, 127(Pt 1): 85-100.
31. Massimi M, Ragusa F, Cardarelli S, et al. Targeting cyclic AMP signalling in hepatocellular carcinoma. Cells, 2019, 8(12): 1511. doi: 10.3390/cells8121511.
32. Yu H, Wu X, Liu Y, et al. Single-gene mutations in hepatocellular carcinoma: applications and challenges in precision medicine. Int J Med Sci, 2025, 22(13): 3268-3276.
33. Liu M, Wen Y. Point-of-care testing for early-stage liver cancer diagnosis and personalized medicine: Biomarkers, current technologies and perspectives. Heliyon, 2024, 10(19): e38444. doi: 10.1016/j.heliyon.2024.e38444.
34. Wang F, Breslin S J P, Qiu W. Novel oncogenes and tumor suppressor genes in hepatocellular carcinoma. Liver Res, 2021, 5(4): 195-203.
35. Li J, Bai L, Xin Z, et al. TERT-TP53 mutations: a novel biomarker pair for hepatocellular carcinoma recurrence and prognosis. Sci Rep, 2025, 15(1): 3620. doi: 10.1038/s41598-025-87545-z.
36. Qiao Y, Wang J, Karagoz E, et al. Axis inhibition protein 1 (Axin1) deletion-induced hepatocarcinogenesis requires intact β-catenin but not Notch cascade in mice. Hepatology, 2019, 70(6): 2003-2017.
37. Xu C, Xu Z, Zhang Y, et al. β-Catenin signaling in hepatocellular carcinoma. J Clin Invest, 2022, 132(4): e154515. doi: 10.1172/JCI154515.
38. Yan B, Peng Z, Xing C. SORBS2, mediated by MEF2D, suppresses the metastasis of human hepatocellular carcinoma by inhibitiing the c-Abl-ERK signaling pathway. Am J Cancer Res, 2019, 9(12): 2706-2718.
39. Rahimi-Farsi N, Bostanian F, Shahbazi T, et al. Novel oncogenes and tumor suppressor genes in Hepatocellular Carcinoma: Carcinogenesis, progression, and therapeutic targets. Gene, 2025, 941: 149229. doi: 10.1016/j.gene.2025.149229.
40. Khorkova O, Stahl J, Joji A, et al. Amplifying gene expression with RNA-targeted therapeutics. Nat Rev Drug Discov, 2023, 22(7): 539-561.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

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