Published online Aug 15, 2026. doi: 10.4251/wjgo.119834
Revised: February 19, 2026
Accepted: May 6, 2026
Published online: August 15, 2026
Processing time: 181 Days and 20 Hours
Eukaryotic DNA replication constitutes a core mechanism underlying cellular proliferation, whereas unrestrained DNA replication is widely recognized as a key driver of tumorigenesis. MCM10 plays an essential role in the initiation of DNA replication.
To explore the biological function of MCM10 in the progression of hepatocellular carcinoma (HCC).
Immunohistochemical staining and large-scale data mining were employed to assess the association between MCM10 expression and clinical pathological characteristics in HCC. Furthermore, in vitro and in vivo experiments were performed to investigate the biological roles and underlying molecular mechanisms of MCM10 in HCC.
Elevated MCM10 expression was significantly associated with adverse clinicopathological features in HCC. High MCM10 expression levels predicted poorer clinical outcomes among patients with HCC. Functionally, upregulation of MCM10 significantly accelerated cellular proliferation in vitro and tumor formation in vivo. Conversely, MCM10 knockdown markedly suppressed HCC cell proliferation and oncogenic activity. Mechanistic investigations revealed that MCM10 promoted cell cycle progression by activating the cyclin D1-CDK4/6 signaling axis. Notably, time-dependent receiver operating characteristic curve analysis demonstrated that the combined detec
MCM10 facilitates HCC progression by activating the cyclin D1-CDK4/6 pathway, supporting a synergistic pro
Core Tip: DNA replication constitutes a core mechanism underlying cell proliferation, whereas unrestrained DNA replication is a pivotal driving force in tumorigenesis. This study aimed to explore the biological function of the conserved replication regulator MCM10 in hepatocellular carcinoma (HCC). Upregulated MCM10 expression correlated with adverse clinicopathological features and inferior survival prognosis. Silencing of MCM10 significantly diminished HCC cell proliferation and oncogenic potential. Furthermore, Cyclin D1 was modulated by MCM10, and the combined evaluation of MCM10 and cyclin D1 showed superior prognostic performance in HCC patients. These findings underscore the synergistic value of the MCM10cyclin D1 molecular axis as a combined biomarker panel for prognostic prediction in HCC.
- Citation: Chen YR, Wang G, He LJ, Ye HW, Wang LF, Zou DD, Wang MQ, Xie HW, Zhu SL, Wang XY. MCM10 promotes hepatocellular carcinoma progression through cyclin D1 regulation. World J Gastrointest Oncol 2026; 18(8): 119834
- URL: https://www.wjgnet.com/1948-5204/full/v18/i8/119834.htm
- DOI: https://dx.doi.org/10.4251/wjgo.119834
Hepatocellular carcinoma (HCC) ranks among the most common malignant tumors globally[1,2]. In China, patients with HCC account for more than half of all cases worldwide, a distribution largely related to hepatitis B virus (HBV) infection[3]. HCC pathogenesis is a complex and multi-step process, characterized by persistent inflammatory damage and progressive hepatic fibrosis. Patients with HBV-related liver cirrhosis carry a significantly increased risk of HCC onset, which is a major cause of death in this population[4]. Despite progress in imaging diagnosis, surgical treatment and adjuvant therapy, the long-term prognosis of HCC patients remains poor[5]. Accordingly, identifying effective prognostic biomarkers and developing optimized therapeutic regimens is of great importance for the clinical management of HCC.
DNA replication in eukaryotic organisms constitutes a fundamental process governing cellular proliferation, and dysregulated or unrestrained DNA replication has been established as a critical driver of tumorigenesis and cancer progression[6,7]. The MCM protein family represents an evolutionarily conserved gene family with a central role in the initiation and elongation stages of genomic DNA replication[8,9]. This family encompasses nine highly conserved subunits, designated MCM2-10. Among these, the MCM2-7 complex functions as the replicative helicase, mediating replication origin licensing, replication initiation, and the progression of DNA synthesis[10]. The MCM8-9 complex is involved in the homologous recombination-mediated DNA double-strand break repair process[11]. MCM10 facilitates the initiation of DNA replication through direct interactions with the MCM2-7 helicase and cell division cycle 45[12].
Recently, aberrant expression of certain MCM proteins has been reported to contribute to HCC tumorigenesis. For example, MCM6 has been identified as a serum biomarker for early recurrence after curative hepatectomy in HCC patients, as it facilitates tumor metastasis through regulation of the MEK/ERK signaling pathway[13]. MCM3 acts as a novel therapeutic target that induces HCC radioresistance by activating the NF-κB pathway[14]. Additionally, MCM7 expression is inversely related to unfavorable prognosis in HCC, and the use of p38 and ERK inhibitors to block the MAPK signaling pathway in MCM7-overexpressing cells effectively suppressed HCC cell proliferation[15]. Based on publicly accessible databases, we previously performed bioinformatics analyses on MCM10, including examination of its expression profile in HCC patients, its prognostic value, and the prediction of related signaling pathways[16]. Our findings strongly suggested the prognostic potential of MCM10. However, the specific biological functions of MCM10 in HCC remain unclear. In this study, we explored the biological effects and downstream signaling molecules of MCM10 in HCC. We found that MCM10 upregulated cyclin D1 expression and accelerated cell cycle progression. Our study also confirmed the value of combining MCM10 and cyclin D1 for prognostic prediction in HCC patients.
A total of 147 pairs of paraffin-embedded HCC samples, including tumor and adjacent nontumor liver tissues, were collected from Sun Yat-sen University Cancer Center (Guangzhou, China) between June 2011 and December 2012. All of the patients underwent curative resection and did not receive other anticancer therapy before surgery or have previous malignant diseases. HCC diagnosis was validated by pathological examination. The final follow-up assessment was conducted on June 30, 2021. The median follow-up period was 73.0 months. The overall survival (OS) was calculated from the date of surgery to the date of death or last follow-up. In addition, 16 fresh HCC tissue specimens were obtained from the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). In this study, all specimens were obtained and used under protocols approved by the institutional review board of Zhujiang Hospital of Southern Medical University, Guangzhou, China.
Immunohistochemistry (IHC) study was performed according to a standard streptavidin-biotin-peroxidase complex method. Paraffin-embedded sections were dewaxed with xylene and blocked in 3% hydrogen peroxide solution. Antigens were extracted in a pressure cooker with EDTA buffer (pH 8.0) for 8 minutes. The slides were incubated overnight with primary antibody against MCM10 (1:100, ab3733, Abcam, United States) or cyclin D1 (1:200, ab16663, Abcam, United States) at 4 °C. Nuclei were counterstained with Meyer’s hematoxylin. Staining intensity was rated as 0 (negative),
The immortalized hepatocyte cell line LO2 and seven HCC cell lines (Huh7, Hep3B, HCCLM3, SNU398, HepG2, SMMC7721, and MHCC97H) were obtained from the Chinese Academy of Sciences Cell Bank (Shanghai, China). 293FT cells were purchased from Invitrogen (Carlsbad, CA, United States). All cells were maintained in high-glucose DMEM (Gibco, United States) supplemented with 10% fetal bovine serum (Gibco, United States) in a humidified atmosphere of 5% CO2 at 37 °C. The cell lines were authenticated by STR profiling.
Total RNA was isolated from tumor tissues or cells using TRIZOL Reagent (Invitrogen) followed by reverse transcription using the Evo M-MLV RT kit with gDNA for qPCR II (Accurate Biology, China). mRNA levels were detected by quantitative real-time PCR (qRT-PCR) with the SYBR Green method on a Roche LightCycler480. mRNA expression was assayed in triplicate and normalized to 18S mRNA level. Relative levels were calculated using the Comparative-Ct Method (ΔΔCt method). The primers used in qRT-PCR assay were listed in Supplementary Table 1.
Western blot analysis followed a standard protocol (BioRad). Briefly, total proteins were extracted from tissues or cells using RIPA lysis buffer (Cell Signaling Technology, United States) supplemented with Complete Protease Inhibitors and phosphatase inhibitor (Merck, Roche). Whole cell lysates were subsequently separated by electrophoresis with SDS polyacrylamide gel and then transferred to PVDF membranes (Millipore, Bedford, MA, United States). The membrane was blocked with 5% bovine serum albumin (ALB) at room temperature for 1 hour, then the primary antibody was incubated at 4 °C overnight, and the secondary antibody was incubated at room temperature for 1 hour. The antibodies used in this study are listed in Supplementary Table 2.
Human MCM10 cDNA was subcloned into the pSin-EF1α-puro lentiviral vector to generate pSin-EF1α-MCM10 vector (indicated as MCM10), the empty vector was used as the negative control (indicated as Vector). Two short hairpin RNA (shRNA) oligonucleotide sequences against MCM10 were cloned into the PLKO.1 lentiviral vector to generate PLKO.1-MCM10 shRNAs (indicated as shMCM10-1 and shMCM10-2, respectively). The scramble shRNA sequence was cloned into the PLKO.1 vector and used as the negative control (indicated as shNC). The above plasmids were purchased from Kidan Biotech (Guangzhou, China). For lentiviral production, 293FT cells were co-transfected with the PMD2.G, psPAX2 (gag, pol) and pLenti-MCM10 plasmids. The cell lines were transduced with virus, and stable lines were established by puromycin (Sigma-Aldrich) selection. The MCM10 shRNA sequences were as follows: ShMCM10-1, 5′-CCGGGACGGCGACGGTGAATCTTATCTCGAGATAAGATTCACCGTCGCCGTCTTTTT-3′ and shMCM10-2, 5′-CCGGGCCAGAT
Cell viability, clone formation, proliferation, and anchorage-independent growth ability were assessed by Cell Counting Kit-8 (CCK8) assay, foci formation assay, EdU assay, and soft agar assay, respectively. For cell viability, cells were seeded in 96-well plates at a density of 1 × 103 cells per well, and cell growth rate was detected using a CCK8 kit (Dojindo, Kumamoto, Japan) according to the manufacturer’s instructions. In foci formation experiments, 1-2 × 103 cells were seeded in 6-well plates. Two weeks later, cells were washed, fixed, and stained by 1% crystal violet. Cell colonies (> 50 cells/colony) were counted. For the EdU incorporation assay, of 5 × 103 cells/well were seeded into 96-well plates, and proliferating cells were examined using the BeyoClick™ EdU-555 Kit (Beyotime, Guangzhou, China) according to the manufacturer’s protocol. The number of EdU-positive cells in five random fields was counted under a fluorescent microscope. Soft agar colony formation assays were performed to assess the anchorage-independent growth of cancer cells. Cells were mixed with an upper layer of agarose gel placed over a pre-solidified lower agarose layer in 6-well plates. Plates were incubated at 37 °C in a 5% CO2 humidified atmosphere for 14 days to allow colony formation. Colonies (> 32 cells/colony) were photographed under a microscope, counted, and analyzed.
Cells were cultured in 6-well plates and collected for cell cycle (Cell Cycle Assay Kit, Wanleibio, China) according to the manufacturer’s protocols. Cell cycle analysis was performed by Cell Quest software (BD, Franklin Lakes, NJ, United States). Experiments were performed in triplicate.
Animal experiments were approved by the Animal Care and Use Committee of Southern Medical University. MHCC97H and HCCLM3 derivative cells (5 × 106 cells per mouse) were subcutaneously injected into 4-week-old BALB/c female nude mice. The tumor volumes were measured as volume (mm3) = 0.5 × L × W2 with a vernier caliper every 3 days, where W and L referred to the smaller and larger diameter, respectively. Three weeks after injections, mice were euthanized according to the approved mouse protocol. Xenografts were removed and weighed.
Statistical analyses were performed using SPSS software version 23.0 (Chicago, IL, United States) and R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). A paired t-test was used to compare the differences between MCM10 expression in cancer and adjacent precancerous tissues. Pearson’s χ2 test was used to analyze the associations between MCM10 protein expression and clinicopathological parameters. The association between MCM10 and cyclin D1 expression was evaluated by linear regression. Cumulative survival curves were obtained by the Kaplan-Meier method and analyzed by the log-rank test. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors that significantly impacted patient survival. The hazard ratios (HRs) and 95% confidence intervals of the prognostic factors were calculated. Time-dependent receiver operating characteristic (ROC) curves were generated to compare the predictive and prognostic accuracy of either MCM10 or cyclin D1 alone or in combination. Data were shown as mean ± SEM. P < 0.05 was considered statistically significant.
Our previous study demonstrated that MCM10 mRNA and protein expression levels were significantly upregulated in HCC tissues, which was validated using publicly accessible databases and 24 pairs of HCC tissues along with their matched adjacent nontumor liver tissues[16]. To clarify the clinical relevance of MCM10 in HCC, IHC staining was performed on 147 pairs of HCC tissues and adjacent normal liver samples. As illustrated in Figure 1A, MCM10 was predominantly localized in the nuclei of liver cancer cells, whereas very few positive cells were observed in the corresponding nontumor liver tissues. The IHC scores of MCM10 were significantly higher in HCC tissues (Figure 1B, P < 0.05). We also examined MCM10 expression levels in several HCC cell lines, including Huh7, Hep3B, HCCLM3, SNU398, HepG2, SMMC7721, and MHCC97H. Compared with the normal hepatocyte cell line LO2, all cancer cell lines had significantly higher MCM10 protein levels (Figure 1C, P < 0.05). To explore the correlation between MCM10 expression and HCC clinical characteristics, we stratified 147 HCC patients into a high MCM10 expression group (n = 62) and a low MCM10 expression group (n = 85). As presented in Table 1, MCM10 upregulation was significantly associated with more aggressive malignant phenotypes, including elevated alpha-fetoprotein levels (P = 0.031), incomplete tumor capsule (P = 0.050), and advanced tumor stage (T stage: P = 0.034).
| Characteristics | All case | MCM10 expression | P value | |
| Low | High | |||
| Cases | 147 | 85 | 62 | |
| Age (years) | 0.985 | |||
| ≤ 50 | 76 (51.7) | 44 (51.8) | 32 (51.6) | |
| > 50 | 71 (48.3) | 41 (48.2) | 30 (48.4) | |
| Gender | 0.763 | |||
| Male | 129 (87.8) | 74 (87.1) | 55 (88.7) | |
| Female | 18 (12.2) | 11 (12.9) | 7 (11.3) | |
| HBsAg | 0.787 | |||
| Negative | 30 (20.4) | 18 (21.2) | 12 (19.4) | |
| Positive | 117 (79.6) | 67 (78.8) | 50 (80.6) | |
| ALT (U/L) | 0.779 | |||
| ≤ 40 | 81 (55.1) | 46 (54.1) | 35 (56.5) | |
| > 40 | 66 (44.9) | 39 (45.9) | 27 (43.5) | |
| TBil (μmol/L) | 0.165 | |||
| ≤ 17.1 | 110 (74.8) | 60 (70.6) | 50 (80.6) | |
| > 17.1 | 37 (25.2) | 25 (29.4) | 12 (19.4) | |
| PT (s) | 0.348 | |||
| ≤ 13.5 | 131 (89.1) | 74 (87.1) | 57 (91.9) | |
| > 13.5 | 16 (10.9) | 11 (12.9) | 5 (8.1) | |
| ALB (g/L) | 0.885 | |||
| ≥ 35 | 137 (93.2) | 79 (92.9) | 58 (93.5) | |
| < 35 | 10 (6.8) | 6 (7.1) | 4 (6.5) | |
| AFP (ng/mL) | 0.031 | |||
| ≤ 200 | 93 (63.3) | 60 (70.6) | 33 (53.2) | |
| > 200 | 54 (36.7) | 25 (29.4) | 29 (46.8) | |
| Capsule integrity | 0.050 | |||
| Complete | 66 (44.9) | 44 (51.8) | 22 (35.5) | |
| No/incomplete | 81 (55.1) | 41 (48.2) | 40 (64.5) | |
| Tumor number | 0.635 | |||
| Single | 105 (71.4) | 62 (72.9) | 43 (69.4) | |
| Multiple (≥ 2) | 42 (28.6) | 23 (27.1) | 19 (30.6) | |
| Tumor differentiation | 0.889 | |||
| I-II | 82 (55.8) | 47 (55.3) | 35 (56.5) | |
| III-IV | 65 (44.2) | 38 (44.7) | 27 (43.5) | |
| Tumor size | 0.721 | |||
| ≤ 5 cm | 57 (38.8) | 34 (40.0) | 23 (37.1) | |
| > 5 cm | 90 (61.2) | 51 (60.0) | 39 (62.9) | |
| T stage | 0.034 | |||
| T1-T2 | 106 (72.1) | 67 (78.8) | 39 (62.9) | |
| T3-T4 | 41 (27.9) | 18 (21.2) | 23 (37.1) | |
| Vascular invasion | 0.080 | |||
| No | 106 (72.1) | 66 (71.8) | 40 (72.6) | |
| Yes | 41 (27.9) | 19 (28.2) | 22 (27.4) | |
| BCLC stage | 0.280 | |||
| A-B | 102 (69.4) | 56 (65.9) | 46 (74.2) | |
| C | 45 (30.6) | 29 (34.1) | 16 (25.8) | |
We performed univariate and multivariate analyses to evaluate the individual and independent prognostic values of MCM10 expression and clinicopathological characteristics in HCC patients (Supplementary Table 3). The results revealed that ALB level (HR 3.771, P = 0.007), tumor capsule integrity (HR 2.388, P = 0.005), tumor differentiation (HR 1.849, P = 0.038), and MCM10 expression (HR 1.821, P = 0.043) were independent unfavorable prognostic factors for OS in HCC patients. Furthermore, Kaplan-Meier survival analysis was conducted to assess the effect of MCM10 expression levels on OS. The results showed that patients with high MCM10 expression had significantly unfavorable OS compared with those with low MCM10 expression (log-rank P = 0.040, Figure 1D).
Similarly, after stratifying HCC patients according to demographic and clinicopathological characteristics, MCM10 expression was consistently associated with clinical outcomes. As presented in Table 2, the risk of death was lower in patients with MCM10 downregulation, particularly among those with less aggressive malignant phenotypes, including younger age (≤ 50 years) (HR 2.322, P = 0.026), lower alanine aminotransferase level (≤ 40 U/L) (HR 2.002, P = 0.032), higher ALB level ( ≥ 35 g/L) (HR 1.717, P = 0.048), and incomplete or absent tumor capsule (HR 1.863, P = 0.048). However, the prognostic value of MCM10 was also evident in patients with tumor size > 5 cm (HR 2.383, P = 0.005) or advanced Barcelona Clinic Liver Cancer (BCLC) stage (HR 2.414, P = 0.036). Furthermore, Kaplan-Meier survival analysis confirmed more favorable clinical outcomes in patients with low MCM10 expression across the aforementioned subgroups (Figure 1E).
| Variables | All case | MCM10low | MCM10high | HR (95%CI)1 | P value1 | ||
| Case number | MST (months) | Case number | MST (months) | ||||
| Cases | 147 | 85 | 87.0 | 62 | 46.5 | 1.692 (1.015-2.819) | 0.044 |
| Age (years) | |||||||
| ≤ 50 | 76 | 44 | 87.0 | 32 | 48.0 | 2.322 (1.105-4.880) | 0.026 |
| > 50 | 71 | 41 | 87.0 | 30 | 46.0 | 1.301 (0.636-2.661) | 0.470 |
| Gender | |||||||
| Male | 129 | 74 | 89.0 | 55 | 51.0 | 1.682 (0.956-2.957) | 0.071 |
| Female | 18 | 11 | 45.0 | 7 | 28.0 | 1.814 (0.549-5.996) | 0.329 |
| HBsAg | |||||||
| Negative | 30 | 18 | 90.0 | 12 | 53.0 | 1.604 (0.607-4.241) | 0.341 |
| Positive | 117 | 67 | 69.0 | 50 | 20.5 | 1.802 (0.987-3.291) | 0.055 |
| ALT (U/L) | |||||||
| ≤ 40 | 81 | 46 | 88.0 | 35 | 44.0 | 2.002 (1.061-3.778) | 0.032 |
| > 40 | 66 | 39 | 85.0 | 27 | 57.0 | 1.220 (0.504-2.951) | 0.659 |
| TBIL (μmol/L) | |||||||
| ≤ 17.1 | 110 | 60 | 86.0 | 50 | 46.5 | 1.551 (0.873-2.756) | 0.135 |
| > 17.1 | 37 | 25 | 89.0 | 12 | 46.0 | 0.604 (0.071-5.172) | 0.646 |
| PT (s) | |||||||
| ≤ 13.5 | 131 | 74 | 89.0 | 57 | 51.0 | 1.635 (0.946-2.826) | 0.078 |
| > 13.5 | 16 | 11 | 79.0 | 5 | 10.0 | 4.397 (0.921-21.000) | 0.063 |
| ALB (g/L) | |||||||
| ≥ 35 | 137 | 79 | 87.0 | 58 | 52.0 | 1.717 (1.004-2.936) | 0.048 |
| < 35 | 10 | 6 | 67.0 | 4 | 6.5 | 2.594 (0.354-18.991) | 0.348 |
| AFP (ng/mL) | |||||||
| ≤ 200 | 93 | 60 | 89.5 | 33 | 53.0 | 1.425 (0.698-2.906) | 0.331 |
| > 200 | 54 | 25 | 67.0 | 29 | 28.0 | 1.745 (0.803-3.794) | 0.160 |
| Capsule integrity | |||||||
| Complete | 66 | 44 | 100.0 | 22 | 81.5 | 1.094 (0.410-2.918) | 0.857 |
| No/incomplete | 81 | 41 | 71.0 | 40 | 20.5 | 1.863 (1.006-3.452) | 0.048 |
| Tumor number | |||||||
| Single | 105 | 62 | 96.0 | 43 | 55.0 | 1.646 (0.827-3.277) | 0.156 |
| Multiple (≥ 2) | 42 | 23 | 58.0 | 19 | 23.0 | 1.752 (0.814-3.770) | 0.151 |
| Tumor differentiation | |||||||
| I-II | 82 | 47 | 99.0 | 35 | 55.0 | 1.591 (0.742-3.412) | 0.233 |
| III-IV | 65 | 38 | 73.5 | 27 | 28.0 | 1.751 (0.881-3.482) | 0.110 |
| Tumor size | |||||||
| ≤ 5 cm | 57 | 34 | 85.0 | 23 | 74.0 | 0.729 (0.256-2.077) | 0.554 |
| > 5 cm | 90 | 51 | 89.0 | 39 | 20.0 | 2.383 (1.302-4.362) | 0.005 |
| T stage | |||||||
| T1-T2 | 106 | 67 | 85.0 | 39 | 62.0 | 1.454 (0.757-2.794) | 0.261 |
| T3-T4 | 41 | 18 | 101.5 | 23 | 21.0 | 1.729 (0.730-4.096) | 0.213 |
| Vascular invasion | |||||||
| No | 106 | 66 | 86.0 | 40 | 60.5 | 1.393 (0.724-2.679) | 0.321 |
| Yes | 41 | 19 | 89.0 | 22 | 20.0 | 2.130 (0.900-5.039) | 0.085 |
| BCLC stage | |||||||
| A-B | 102 | 56 | 96.0 | 46 | 54.0 | 1.645 (0.851-3.179) | 0.139 |
| C | 45 | 29 | 84.0 | 16 | 15.0 | 2.414 (1.060-5.497) | 0.036 |
Because MCM10 exhibited relatively higher expression in MHCC97H and SMMC7721 cells and lower expression in Hep3B and HCCLM3 cells (Figure 1C), we established stable MCM10 knockdown MHCC97H and SMMC7721 cell lines (Figure 2A and B) and stable MCM10 overexpression Hep3B and HCCLM3 cell lines (Figure 3A and B). qRT-PCR and western blot analysis revealed that MCM10 expression was reduced by more than fourfold in MHCC97H and SMMC7721 cells transfected with shMCM10-1 compared with the shNC group. Therefore, we selected shMCM10-1 as the most effective shRNA and used it for subsequent experiments. CCK-8 assays, colony formation assays, and EdU incorporation assays demonstrated that MCM10 knockdown significantly inhibited cancer cell viability and proliferation (Figure 2C-E, P < 0.05). Soft agar assays further revealed that MCM10 knockdown suppressed the anchorage-independent growth capacity of HCC cells (Figure 2F, P < 0.05). We further explored the effect of MCM10 on HCC growth in vivo. MHCC97H cells with stable MCM10 knockdown (MHCC97H-shMCM10-1) or negative control (MHCC97H-shNC) were sub
Using the STRING online platform, we previously constructed a functional protein-protein interaction network of MCM10 and verified its critical role in DNA replication[16]. However, the regulatory effects of MCM10 and its downstream target genes in HCC remain largely unknown. To explore the molecular mechanism of MCM10 in HCC, we analyzed HCC specimens from The Cancer Genome Atlas (TCGA) database and stratified samples according to MCM10 expression levels. Gene Set Enrichment Analysis was conducted on the highest and lowest quartiles of HCC samples, and the results revealed that MCM10 was positively correlated with the cell cycle pathway (Figure 4A). As presented in Figure 4B and C, flow cytometric analysis demonstrated that shMCM10-1-transfected cells had an increased proportion of cells in the G0/G1 phase and a decreased proportion in the S phase compared with control cells. These results indicate that MCM10 knockdown impedes cell cycle progression and induces G1 phase arrest in HCC cells.
To identify the regulatory pathway through which MCM10 mediates G1 phase arrest, we employed qRT-PCR to screen G1/S checkpoint-associated cell cycle regulators[17]. As shown in Figure 4D, CCND1 expression decreased by approximately twofold in MCM10-knockdown cells. Moreover, the cyclin D1 inhibitors p21 and p27 were upregulated, whereas the downstream targets of cyclin D1 CDK4 and CDK6 and the transcription factor E2F1[18] were downregulated in shMCM10-1-transfected cells. Consistently, cyclin D1, CDK4, CDK6, and pRB protein expression was reduced, while p21 and p27 protein expression was elevated (Figure 4E). These findings suggest that cyclin D1 serves a pivotal role in MCM10-mediated cell cycle progression.
To further validate the regulatory effect of MCM10 on cyclin D1 in clinical specimens, we used the Genotype Tissue Expression project (https://www.gtexportal.org/) and the TCGA network (http://cancergenome.nih.gov/) to analyze the correlation between these two genes. We found that MCM10 was significantly positively correlated with CCND1 at the mRNA level across most normal and malignant tissues (Figure 5A and B). IHC staining revealed that cyclin D1 protein expression in HCC tissues with high MCM10 expression was markedly higher than in tissues with low MCM10 expression (Figure 5C, P < 0.05). Furthermore, HCC tissues with high MCM10 expression showed a higher positive rate of cyclin D1 than those with low MCM10 expression (39/62 vs 37/87, Figure 5D). Western blot analysis of 16 fresh HCC samples further confirmed that MCM10 expression was associated with cyclin D1 expression (Figure 5E, P = 0.0103), suggesting that the MCM10-cyclin D1 axis is involved in HCC progression.
The important roles of MCM10 and cyclin D1 in HCC pathogenesis have been verified in vitro and in vivo, supporting their prognostic predictive potential in this malignancy. To further assess their prognostic value, we constructed time-dependent ROC curves for MCM10 alone, cyclin D1 alone, and MCM10 and cyclin D1 together, and compared their sequential HR trends for survival using data from 147 HCC patients. As presented in Figure 5F, the combination of MCM10 and cyclin D1 was modestly but consistently superior to either marker alone in predicting the OS of patients with HCC across the entire observation period. Compared with patients with low expression of both MCM10 and cyclin D1, those with other expression profiles showed a significantly higher risk of HCC-related mortality (HR 2.426, P = 0.005) (Table 3 and Supplementary Table 4). Furthermore, KaplanMeier analysis demonstrated that HCC patients with either high MCM10 or high cyclin D1 expression had markedly shorter OS than those with low expression of both markers (logrank P = 0.0035, Figure 5G). Figure 5H displays the prognostic performance of the MCM10-cyclin D1 combination in various patient subgroups. Patients with low expression of both MCM10 and cyclin D1 presented a comparatively lower mortality risk, particularly in subgroups with less aggressive features, including total bilirubin level ≤ 17.1 μmol/L (HR 2.183, P = 0.029), prothrombin time ≤ 13.5 seconds (HR 2.173, P = 0.019), ALB level ≥ 35 g/L (HR 2.083, P = 0.022), absence of vascular invasion (HR 2.059, P = 0.044), and BCLC stage A-B (HR 2.546, P = 0.020). These results indicate that combined low levels of MCM10 and cyclin D1 can serve as a new indicator for relatively early-stage HCC.
| Variables | All case | MCM10low and Cyclin D1low | MCM10high or Cyclin D1high | HR (95%CI)1 | P value1 | ||
| Case number | MST (months) | Case number | MST (months) | ||||
| Cases | 147 | 48 | 100.0 | 99 | 53.0 | 2.426 (1.309-4.496) | 0.005 |
| Age (years) | |||||||
| ≤ 50 | 76 | 31 | 89.0 | 45 | 53.0 | 1.838 (0.850-3.975) | 0.122 |
| > 50 | 71 | 17 | 110.0 | 54 | 55.0 | 4.167 (1.261-13.768) | 0.019 |
| Gender | |||||||
| Male | 129 | 43 | 108.0 | 86 | 53.0 | 3.270 (1.579-6.771) | 0.001 |
| Female | 18 | 5 | 27.0 | 13 | 45.0 | 0.474 (0.130-1.735) | 0.260 |
| HBsAg | |||||||
| Negative | 30 | 10 | 62.5 | 20 | 34.5 | 1.647 (0.578-4.691) | 0.350 |
| Positive | 117 | 38 | 106.5 | 79 | 55.0 | 2.932 (1.356-6.341) | 0.006 |
| ALT (U/L) | |||||||
| ≤ 40 | 81 | 26 | 96.5 | 55 | 51.0 | 1.892 (0.919-3.894) | 0.084 |
| > 40 | 66 | 22 | 104.0 | 44 | 55.0 | 4.223 (1.238-14.401) | 0.021 |
| TBIL (μmol/L) | |||||||
| ≤ 17.1 | 110 | 34 | 96.5 | 76 | 50.5 | 2.183 (1.083-4.401) | 0.029 |
| > 17.1 | 37 | 14 | 105.0 | 23 | 73.0 | 3.182 (0.864-11.722) | 0.082 |
| PT (s) | |||||||
| ≤ 13.5 | 131 | 43 | 100.0 | 88 | 56.0 | 2.173 (1.138-4.150) | 0.019 |
| > 13.5 | 16 | 5 | 100.0 | 11 | 24.0 | 5.565 (0.664-46.619) | 0.113 |
| ALB (g/L) | |||||||
| ≥ 35 | 137 | 46 | 96.5 | 91 | 57.0 | 2.083 (1.114-3.895) | 0.022 |
| < 35 | 10 | 2 | 116.0 | 8 | 10.0 | 58.055 (0.049-68429) | 0.260 |
| AFP (ng/mL) | |||||||
| ≤ 200 | 93 | 35 | 100.0 | 58 | 72.0 | 1.495 (0.723-3.090) | 0.278 |
| > 200 | 54 | 13 | 110.0 | 41 | 36.0 | 6.531 (1.536-27.765) | 0.011 |
| Capsule integrity | |||||||
| Complete | 66 | 24 | 100.0 | 42 | 91.5 | 1.211 (0.454-3.230) | 0.701 |
| No/incomplete | 81 | 24 | 97.0 | 57 | 27.0 | 3.871 (1.693-8.852) | 0.001 |
| Tumor number | |||||||
| Single | 105 | 38 | 106.5 | 67 | 72.0 | 1.954 (0.905-4.216) | 0.088 |
| Multiple (≥ 2) | 42 | 10 | 69.0 | 32 | 27.5 | 2.841 (0.979-8.249) | 0.055 |
| Tumor differentiation | |||||||
| I-II | 82 | 28 | 107.5 | 54 | 69.0 | 2.363 (0.951-5.873) | 0.064 |
| III-IV | 65 | 20 | 87.0 | 45 | 36.0 | 2.373 (1.026-5.487) | 0.043 |
| Tumor size | |||||||
| ≤ 5 cm | 57 | 24 | 82.5 | 33 | 82.0 | 0.678 (0.261-1.760) | 0.425 |
| > 5 cm | 90 | 24 | 110.0 | 66 | 35.0 | 5.575 (1.984-15.666) | 0.001 |
| T stage | |||||||
| T1-T2 | 106 | 43 | 100.0 | 63 | 76.0 | 1.518 (0.731-3.153) | 0.263 |
| T3-T4 | 41 | 5 | 100.0 | 36 | 19.0 | 3.776 (0.881-16.193) | 0.074 |
| Vascular invasion | |||||||
| No | 106 | 41 | 100.0 | 65 | 67.0 | 2.059 (1.018-4.163) | 0.044 |
| Yes | 41 | 7 | 110.0 | 34 | 26.0 | 2.875 (0.669-12.360) | 0.156 |
| BCLC stage | |||||||
| A-B | 102 | 35 | 108.0 | 67 | 55.0 | 2.546 (1.155-5.609) | 0.020 |
| C | 45 | 13 | 89.0 | 32 | 45.0 | 2.091 (0.779-5.613) | 0.143 |
In the present study, we identified MCM10 as a key oncogenic regulator with a critical role in HCC progression and elucidated the molecular mechanism underlying its biological functions in HCC. IHC staining demonstrated that elevated MCM10 expression was associated with adverse clinicopathological features and poor clinical outcomes in HCC patients. Depletion of MCM10 inhibited HCC cell viability and proliferation in vitro, as well as tumorigenicity in vivo. Mechanistic analyses revealed that MCM10 upregulates cyclin D1 expression, thereby promoting cell cycle progression. Moreover, this regulatory interaction was supported by the positive correlation between MCM10 and cyclin D1 expression in HCC tissues. The combination of MCM10 and cyclin D1 exhibited substantial prognostic value in patients with HCC. Collectively, these findings highlight that MCM10 and its downstream effector cyclin D1 hold significant potential as prognostic biomarkers for HCC. Although the oncogenic role of MCM10 in DNA replication has been well established, our study further extends this knowledge by demonstrating that MCM10 regulates the cyclin D1-CDK4/6 axis, which drives G1/S phase transition and promotes HCC cell proliferation. This finding establishes a critical link between the DNA replication machinery and cell cycle regulation during hepatocarcinogenesis.
Enabling replicative immortality is a key hallmark of cancer[6,7]. DNA replication is a tightly regulated process that ensures the accurate duplication of the eukaryotic genome and occurs only once during each cell cycle. Its dysregulation can lead to genomic instability, thereby triggering uncontrolled replication and cancer development[19,20]. In cancer cells, the expression of many proteins involved in DNA replication is abnormally regulated. MCM10, a replication licensing factor, functions as a DNA-binding scaffold to protect against replication stress and maintain genomic integrity during cell cycle progression. It is upregulated in various malignancies and can serve as a potential proliferation marker[21-24]. Wan et al[25] showed that MCM10 is upregulated in HCC cell lines and that silencing MCM10 can inhibit cell proliferation. Lei et al[26] reported increased MCM10 protein expression in HCC tissues through IHC staining. Consistent with previous reports, our study confirms that MCM10 is upregulated in HCC and contributes to malignant progression. However, we further identified that cyclin D1 is a key downstream target of MCM10 in HCC. This finding has not been previously reported and provides new insights into the MCM10-mediated cell cycle regulatory network.
Recently, several lines of research have reported the oncogenic role and molecular mechanism of MCM10 in cancer development. Fatoba et al[27] reported that human MCM10 is an acetylated protein regulated by SIRT1, which binds and deacetylates MCM10, thereby modulating MCM10 stability and its DNA-binding capacity. In breast cancer, MCM10 may promote cell invasiveness and migration through the Wnt/β-catenin pathway, and its high expression is positively correlated with poor prognosis[28]. A follow-up study further revealed that MCM10 expression in breast cancer is also regulated by the estrogen receptor (ER) signaling pathway, with its expression being inhibited by ER blockade or serum starvation[29]. Moreover, Zhang et al[30] recently reported that MCM10 expression is elevated in sorafenib-resistant HCC cell lines, and knockout of MCM10 reduces cancer stemness and restores sorafenib sensitivity in resistant cancer cells. Our mechanistic investigations demonstrated that silencing MCM10 induces cell cycle arrest in HCC cells by downregulating cyclin D1, thereby inhibiting tumor growth.
It is well known that during mitosis, numerous cell cycle-related genes are involved in regulating the transition from G1 to S phase[17]. We hypothesized that cyclin D1 is a target of MCM10 that promotes cell cycle progression. As a mitotic sensor of cell cycle machinery, cyclin D1 accumulates and activates CDK4/6 in response to mitogenic growth factors in early- to mid-G1[31]. The resulting cyclin D1-dependent kinase initiates the phosphorylation-dependent inactivation of the retinoblastoma (RB) tumor suppressor protein. This process separates E2F1 from the RB-E2F complex and thereby influences the regulation of G1/S transition by E2F1 target genes[32]. Extensive studies have confirmed that cyclin D1 upregulation in cancer cells is responsible for DNA damage and chromosomal abnormalities[33-35]. In this study, we found a high correlation between MCM10 and cyclin D1 in 147 HCC patients (via IHC staining) and 16 fresh HCC samples (via western blot). Furthermore, silencing MCM10 decreased cyclin D1, CDK4, and CDK6 expression in the G1/S phase of HCC cells, suggesting a pivotal role of MCM10 in regulating the cell cycle.
In view of the important regulatory relationship between MCM10 and cyclin D1, we conducted further studies to investigate the prognostic value of the combination of these two genes in patients with HCC. Time-dependent ROC analysis is used to evaluate the discriminatory power of continuous indicators for time-dependent disease outcomes[36]. As expected, time-dependent ROC analysis showed that the combination of MCM10 and cyclin D1 was consistently slightly superior to either MCM10 alone or cyclin D1 alone in predicting survival throughout the observation period. Although our sample size was relatively small, limiting the effectiveness of certain stratified analyses, we identified the potential of MCM10 and cyclin D1 as prognostic indicators for HCC. It is important to conduct further verification with a larger sample size. This finding suggests that the MCM10-cyclin D1 axis may serve as a promising prognostic panel for risk stratification in HCC patients, especially in the early-stage population.
Although we found that the molecular biomarker MCM10-cyclin D1 has a synergistic effect in predicting the survival rate of patients with HCC, potential limitations also need to be considered. Firstly, our study lacks mechanistic depth and fails to clarify the direct molecular mechanism by which MCM10 regulates cyclin D1. This may affect the clarity of the interaction between the two genes. Secondly, we conducted a series of experiments with HCC cell lines but did not perform functional validation using primary HCC cells. This might not be sufficient to resemble the biological characteristics of in vivo tumors. Thirdly, our model fails to replicate the liver-specific microenvironment of HCC and cannot assess the impact of molecules on its invasive metastasis. An in situ tumorigenesis model should be established in the future.
In summary, our study reveals that MCM10 promotes cell viability and proliferation by activating cyclin D1. MCM10 overexpression in HCC tissues is significantly correlated with poor clinical outcomes. Additionally, the combined use of MCM10 and cyclin D1 as molecular biomarkers exhibits a synergistic effect in predicting the survival of HCC patients. MCM10 may have significant potential as a therapeutic target for HCC.
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