Hepatocellular carcinoma (HCC) remains one of the most formidable challenges in oncology, notably within Egypt—the nation where it is the leading cause of cancer morbidity and mortality—and globally. Despite advances in imaging and therapeutic interventions, the quest for reliable, non-invasive biomarkers that can enhance early detection and predict prognosis in HCC has been ongoing. A groundbreaking study recently published in the journal Gene Expression brings new insights by examining the role of serum-derived circular RNA, specifically hsa_circ_101555, as both a diagnostic and prognostic marker in HCC patients.
Circular RNAs (circRNAs) have emerged as a novel class of endogenous non-coding RNAs characterized by covalently closed loop structures, devoid of 5’ caps and 3’ polyadenylated tails, conferring exceptional stability in biological fluids. Their unique configuration resists exonuclease-mediated degradation, thereby positioning circRNAs as highly promising candidates in cancer biomarker research. While circRNAs have been implicated in various cancer biology mechanisms, their clinical utility, particularly in hepatocellular carcinoma, remains largely under-explored, making this study a pioneering endeavor.
In this pivotal cross-sectional analysis, researchers measured serum levels of hsa_circ_101555 using quantitative real-time polymerase chain reaction (qRT-PCR) among 62 Egyptian patients clinically and radiologically diagnosed with HCC, juxtaposed against 30 healthy controls. Measurements were taken at baseline prior to treatment and subsequently three months post-therapy, enabling a dynamic assessment of circRNA expression in relation to tumor behavior and therapeutic response.
Strikingly, the study revealed a profoundly elevated mean expression level of hsa_circ_101555 in HCC patients (7.66 ± 3.74) relative to healthy individuals (1.21 ± 0.96). Such a significant differential underscores the potential diagnostic value of this circRNA in distinguishing malignant from non-malignant hepatic states. Receiver operating characteristic (ROC) analyses further substantiated this premise, highlighting an exceptional discriminatory capacity with an area under the curve (AUC) of 0.984 at a threshold value of 1.966, thus exhibiting almost perfect accuracy.
Beyond diagnosis, hsa_circ_101555 demonstrated considerable prognostic relevance. Its post-interventional serum levels exhibited a notable ability to differentiate between patients showing tumor progression or regression, classified through the Response Evaluation Criteria in Solid Tumors (RECIST) and its modified iteration (mRECIST). At a cutoff of 5.1150, the circRNA yielded an AUC of 0.891, indicative of strong predictive performance for disease trajectory and therapeutic outcomes. This relationship was substantiated through comprehensive statistical assessments reflecting the biomarker’s sensitivity in capturing tumor dynamics.
Delving deeper, the study uncovered significant positive correlations between post-treatment hsa_circ_101555 levels and several established laboratory indices indicative of liver insult and dysfunction. These included the albumin-bilirubin (ALBI) score, where the correlation coefficient (r) was 0.424 (p = 0.001), as well as the neutrophil-to-lymphocyte ratio (NLR) with r = 0.410 (p = 0.001). Additional correlations emerged with alpha-fetoprotein (AFP), aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT), fibrosis-4 (FIB-4) index, and the aspartate aminotransferase to platelet ratio index (APRI), all underscoring the association of hsa_circ_101555 with hepatic inflammation, fibrosis severity, and overall disease burden.
Notably, hsa_circ_101555 levels also correlated with pivotal clinical and pathological tumor characteristics essential for staging and therapeutic decision-making. Elevated circRNA levels were significantly linked to larger tumor size (greater than 5 cm), increased tumor multiplicity (more than three nodules), the presence of vascular invasion, advanced Barcelona Clinic Liver Cancer (BCLC) stage C, and higher Tumor, Node, Metastasis (TNM) staging. These correlations affirm the circRNA’s potential in reflecting tumor aggressiveness and metastatic potential.
The intricate interplay between circRNAs and oncogenic processes has garnered increasing attention, as they can function as microRNA sponges, interact with RNA-binding proteins, and modulate transcriptional and posttranscriptional networks crucial to tumor biology. The upregulation of hsa_circ_101555 observed in this study suggests that it may exert functional roles in hepatocarcinogenesis, potentially contributing to tumor proliferation, invasion, and resistance mechanisms. However, elucidating its exact molecular mechanisms remains an imperative frontier for future translational research.
From a clinical perspective, the identification of serum-based, non-invasive biomarkers such as hsa_circ_101555 carries profound implications. They could complement existing imaging modalities and serological tests, enabling earlier diagnosis, real-time monitoring of therapeutic response, and timely detection of disease progression or recurrence. This is of paramount importance in HCC, where prognosis is often poor due to late presentation and limited effective treatments in advanced stages.
Furthermore, the study presents hsa_circ_101555 as a candidate biomarker customized to the Egyptian population, addressing the regional epidemiological burden of HCC. Given genetic and environmental factors modulating disease prevalence and characteristics across populations, such region-specific biomarkers offer tailored clinical utility and pave the way for personalized medicine approaches in oncology.
Technically, the use of qRT-PCR for circRNA quantification in serum illustrates the assay’s sensitivity and reproducibility for clinical application. The methodology employed underscores robust molecular techniques adapted for biomarker validation, including normalization strategies and data analysis adhering to rigorous statistical standards. These technical advances enable the transition of circRNAs from bench to bedside.
While promising, the study’s cross-sectional design and sample size do suggest caution, emphasizing the need for longitudinal studies with larger cohorts to validate the findings, establish causality, and assess circRNA dynamics over extended treatment timelines. Additionally, integrating multi-omics data encompassing transcriptomic, proteomic, and epigenetic landscapes could illuminate the broader regulatory impact of hsa_circ_101555 in HCC.
In summary, this landmark investigation offers compelling evidence that serum-derived hsa_circ_101555 harbors significant oncogenic and biomarker potential in hepatocellular carcinoma. Its elevated expression correlates robustly with disease presence, severity, progression, and key clinical features. As researchers and clinicians grapple with the complex challenge of HCC management, circRNAs like hsa_circ_101555 may soon emerge as indispensable tools, transforming diagnostic paradigms and enabling more precise prognostication—and ultimately improving patient outcomes.
The groundbreaking implications of this study mark a pivotal step towards harnessing the untapped universe of circular RNAs. With further validation and mechanistic exploration, hsa_circ_101555 may herald a new era in non-invasive cancer biomarker discovery, transforming the landscape of hepatocellular carcinoma diagnosis and prognostication worldwide.
Subject of Research: Hepatocellular carcinoma; circular RNA biomarkers; non-invasive diagnosis and prognosis.
Article Title: The Potential Oncogenic Role of Serum-derived hsa_circ_101555 as a Non-invasive Diagnostic/Prognostic Marker in Patients with Hepatocellular Carcinoma
News Publication Date: 17-Mar-2025
Web References: http://dx.doi.org/10.14218/GE.2025.00012
Keywords: Hepatocellular carcinoma; Circular RNA; hsa_circ_101555; Biomarkers; Diagnosis; Prognosis; Liver cancer; Non-coding RNA; qRT-PCR; Tumor progression; Liver fibrosis; Oncogenic markers
