PACC1 could serve as a prognostic biomarker for patients with hepatocellular carcinoma

Dear Editor, Liver cancer is the sixth most common malignancy worldwide and ranks second in cancer-related mortality[1]. Primary liver cancer includes three major pathological subtypes: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and the less frequent combined hepatocellular-cholangiocarcinoma (cHCC-CCA). According to the GLOBOCAN 2022 statistics, HCC accounts for approximately 75%–85% of cases, whereas iCCA represents 10%–15%[2]. Owing to its asymptomatic early stages, rapid progression, and low rate of early detection, most LIHC patients are diagnosed at advanced stages, missing the optimal window for effective treatment. This highlights the critical need to identify novel biomarkers that could serve both prognostic and therapeutic purposes. Proton-Activated Chloride Channel 1 (PACC1, also known as TMEM206) is a member of the transmembrane (TMEM) protein family[3], several of which have been implicated in tumor initiation, progression, and metastasis[4]. Notably, PACC1 has been shown to contribute to key oncogenic processes in colorectal cancer and is regulated by p53 in a p21-dependent manner[5]. This manuscript is conducted in accordance with the TITAN Guidelines 2025[6]. To elucidate the potential function of PACC1 in liver cancer, we analyzed transcriptomic profiles and matched clinical information from The Cancer Genome Atlas (TCGA-LIHC). We assessed PACC1 expression patterns, explored its prognostic significance, and performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Furthermore, we investigated its association with the tumor immune microenvironment using multiple independent computational algorithms. Table 1 summarizes the baseline clinical characteristics of LIHC patients. Pan-cancer analysis revealed heterogeneous PACC1 expression, with a pronounced upregulation in LIHC tumor tissues relative to normal samples (Fig. 1A-E). High PACC1 expression was significantly associated with advanced histologic stage and T stage (Fig. 1F-G), while statistically significant, the T-stage association is modest and should be interpreted cautiously. Kaplan–Meier survival analysis demonstrated that patients with elevated PACC1 levels had significantly poorer overall survival compared to those with low expression (Fig. 1H). ROC curve analysis showed strong diagnostic potential, with an AUC of 0.963 (Fig. 1I). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicate that PACC1 may be involved in LIHC development through various biological processes and pathways, such as detoxification of copper ion, stress response to copper ion, axonogenesis, mineral absorption, neuroactive ligand–receptor interaction, metabolism of xenobiotics by cytochrome P450, retinol metabolism, ECM–receptor interaction, and IL-17 signaling pathway (Fig. 1J-K). Immune infiltration analysis using five independent algorithms (CIBERSORT, EPIC, MCPcounter, quanTIseq, and TIMER) consistently linked PACC1 expression with altered immune cell landscapes (Fig. 1L-P). Single-cell RNA-seq analysis further revealed that PACC1 is predominantly expressed in natural killer (NK) cells and CD8+T cells in dataset GSE179795, whereas its expression was not detected in dataset GSE125449, suggesting that PACC1 expression may change following PD-L1-targeted therapy (Fig. 1Q-T). Figure 1.: (A) Pan-cancer expression of PACC1 compared with normal tissues based on TCGA data. (B–C) PACC1 expression in unpaired (B) and paired (C) LIHC samples. (D–E) Immunohistochemical staining from the HPA database showing PACC1 in normal liver tissue (D) and LIHC tissue (E). (F–G) Correlations between PACC1 expression and histologic stage and T stage. (H) Kaplan–Meier analysis of overall survival in LIHC patients stratified by PACC1 expression. (I) ROC curve analysis evaluating the diagnostic performance of PACC1. (J–K) GO and KEGG enrichment analyses of differentially expressed genes associated with PACC1 in LIHC. (L–T) Assessment of tumor immune microenvironment and immune cell infiltration linked to PACC1 expression. Statistical signifcance is indicated as *P < 0.05, **P < 0.01, ***P < 0.001. Table 1 - Association of PACC1 expression with clinicopathological features in TCGA-LIHC Characteristics Low expression of PACC1 High expression of PACC1 P-value n 186 188 Pathologic T stage, n (%) 0.038 T1 103 (27.8) 80 (21.6) T2 42 (11.3) 53 (14.3) T3&T4 39 (10.5) 54 (14.6) Pathologic N stage, n (%) 0.681 N0 122 (47.3) 132 (51.2) N1 1 (0.4) 3 (1.2) Pathologic M stage, n (%) 1.000 M0 126 (46.3) 142 (52.2) M1 2 (0.7) 2 (0.7) Gender, n (%) 0.356 Female 56 (15) 65 (17.4) Male 130 (34.8) 123 (32.9) Albumin(g/dL), n (%) 0.192 <3.5 42 (14) 27 (9) ≥3.5 120 (40) 111 (37) Histologic grade, n (%) < 0.001 G1 37 (10) 18 (4.9) G2 97 (26.3) 81 (22) G3 47 (12.7) 77 (20.9) G4 4 (1.1) 8 (2.2) Residual tumor, n (%) 0.038 R0 173 (50.1) 154 (44.6) R1&R2 5 (1.4) 13 (3.8) Figure 1U-W presents a forest plot of the meta-analysis integrating univariate Cox proportional hazards results from TCGA-LIHC and several independent external datasets. The combined results confirm that high PACC1 expression is significantly associated with poorer survival outcomes in liver cancer patients. Notably, its prognostic performance appears to exceed that of widely used biomarkers such as alpha-fetoprotein (AFP) and glypican-3 (GPC3). In conclusion, our study suggests that PACC1 may function as a promising biomarker for both diagnosis and prognosis in LIHC. PACC1, as a chloride channel, may influence cellular stress responses, ion homeostasis, and tumor–immune interactions, which could plausibly link copper stress, xenobiotic metabolism, and immune pathways. These findings warrant further investigation into the potential of PACC1 as a therapeutic target in LIHC. As this study is based solely on bioinformatic analyses, further in vivo and in vitro investigations are warranted to validate the mechanistic functions of PACC1 and assess its potential as a therapeutic target in liver cancer.