Multiple clinical studies have demonstrated that HULC is significantly overexpressed in both plasma and tissue samples from patients with GC compared to healthy controls. Survival analyses have shown that elevated HULC expression is significantly associated with poorer overall survival (53, 54). In addition, circulating HULC levels correlate with tumor size, lymph node involvement, distant metastasis, and Helicobacter pylori infection in GC patients (13, 55). Notably, the combination of HULC expression and H. pylori status improves the predictive accuracy for GC risk (56). These findings suggest that HULC is a promising biomarker for GC diagnosis and prognosis.

In vivo, silencing HULC significantly inhibited tumor growth in a mouse xenograft model of gastric cancer (25). In vitro, overexpression of HULC promotes the proliferation and invasion of human gastric cancer cells, while inhibiting cell apoptosis. Conversely, knockdown of HULC reverses these effects (57). Mechanistically, dual-luciferase reporter assays and RNA pull-down experiments revealed that HULC directly targets miR-9-5p to exert its biological functions. Further studies have demonstrated that HULC enhances proliferation, EMT, migration, and invasion of gastric cancer cells through the miR-9-5p/MYH9 axis (25, 57). Additionally, HULC promotes gastric cancer growth and metastasis by epigenetically suppressing the expression of p53. Specifically, RIP- and ChIP-qPCR assays have shown that HULC recruits EZH2 to the p53 promoter region, mediating its transcriptional repression in gastric cancer cells (58). Moreover, HULC plays a critical role in regulating chemoresistance. Inhibition of HULC enhances cisplatin-induced apoptosis in gastric cancer cells (47), and the HULC/FoxM1 signaling pathway has been shown to promote cisplatin resistance by inducing autophagy (52).

Taken together, these findings highlight HULC as an important regulator of tumor growth, metastasis, and drug resistance in gastric cancer. HULC represents a promising biomarker for early detection and prognosis and may serve as a novel therapeutic target in the prevention and treatment of GC.

Pancreatic cancer ranks as the fourth leading cause of cancer-related deaths in the United States and the sixth in China (14, 27). Bioinformatics analyses have identified HULC as one of the most significantly dysregulated lncRNAs in pancreatic ductal adenocarcinoma cells (27). A clinical study involving tumor and matched normal tissues from 304 PC patients revealed that HULC is highly expressed in both the tissues and serum of PC patients. Notably, elevated HULC levels were significantly associated with larger tumor size, lymph node metastasis, and vascular invasion.

In vivo, using PC xenografts in nude mice demonstrated that HULC knockdown significantly suppressed tumor growth compared to controls (59). Complementary in vitro studies further showed that silencing HULC reduced pancreatic ductal adenocarcinoma cell proliferation, viability, invasion, and migration. HULC knockdown also led to decreased expression of EMT markers(N-cadherin, vimentin, and Snail), while increasing the expression of E-cadherin (59). Mechanistically, HULC appears to promote pancreatic ductal adenocarcinoma progression via multiple pathways. It inhibits YAP activation, thereby promoting autophagy and enhancing tumor cell proliferation (27). Additionally, HULC may facilitate pancreatic ductal adenocarcinoma cell proliferation and invasion through the Wnt/β-catenin signaling pathway (14). HULC also plays a role in intercellular communication through extracellular vesicles, where it promotes invasion and migration by inducing EMT in recipient cells. This effect can be counteracted by miR-622, which targets HULC to suppress EMT-related signaling, providing new insights into pancreatic ductal adenocarcinoma pathogenesis and potential therapeutic targets (60).

Colorectal cancer is one of the main causes of cancer deaths worldwide. By bioinformatics analysis, lncRNA HULC is regarded as a potential biomarker for colorectal cancer (2, 61). Additionally, previous research has demonstrated that serum HULC levels are significantly elevated in patients with CRC compared to healthy individuals. This elevation suggests that HULC may serve as a promising biomarker for the diagnosis of CRC (15). HULC expression was significantly upregulated in human primary colorectal cancer and colorectal cancer cell lines. Kaplan-Meier survival analysis showed that the upregulation of HULC was significantly associated with poor prognosis in patients with colorectal cancer. Knockdown of HULC significantly inhibited the proliferation, migration and invasion of CRC cells and promoted cell apoptosis in vitro. In BALB/c nude mice tumorigenic experiments show that knockdown of HULC can inhibit the proliferation of CRC cells. Mechanically speaking, RNA immunoprecipitation (RIP) and RNA pull-down experiments indicated that in colorectal cancer cells, HULC promoted CRC by directly binding to EZH2 to inhibit the expression of NKD2 (62).

Cholangiocarcinoma (CCA) is a highly fatal malignancy with a poor overall survival rate. Bioinformatics analysis of 36 CCA tumor tissues and 9 normal control tissues from WMU cohort revealed that HULC was significantly upregulated and strongly associated with shorter overall survival in CCA patients (63). Functional assays, including cell migration, and invasion experiments, demonstrated that HULC overexpression enhances the migratory and invasive capacities of CCA cells. Further mechanistic studies showed that HULC acts by targeting miR-372/miR-373, leading to upregulation of inflammation-related genes such as IL-6 and CXCR4. This, in turn, induces aberrant inflammatory responses and promotes cancer cell migration and invasion (64).

HULC is also implicated in the pathogenesis of oral squamous cell carcinoma (OSCC), one of the most prevalent malignancies in the oral and maxillofacial region worldwide (65). In a murine xenograft model, depletion of HULC reduced tumor growth and suppressed EMT. In vitro, HULC knockdown inhibited proliferation, migration, and invasion of OSCC cells, while increasing apoptosis (66). These findings suggest that HULC plays a key role in OSCC tumorigenesis and progression.

In nasopharyngeal carcinoma (NPC), clinical studies have shown that HULC is highly expressed in tumor tissues and is associated with poor patient prognosis. HULC overexpression promotes the growth of NPC cells, whereas its downregulation activates the tumor suppressor p53, increases p21 expression, and induces cell cycle arrest and apoptosis (67). These data support a role for HULC as a carcinogenic lncRNA and highlight its potential as a therapeutic target in NPC.

Although HULC has been strongly implicated in the development and progression of several digestive system cancers, its role in esophageal cancer remains unclear. From 2014 to 2018, comparative analyses of tumor tissues from 95 patients with esophageal cancer and 121 healthy control samples showed no significant association between HULC expression and cancer prognosis across any clinical subgroup (68, 69). This suggests that the contribution of HULC to esophageal cancer may be limited or context-dependent, warranting further investigation.

Digestive system cancers exhibit tumor heterogeneity, both across different cancer types and among individual patients. This heterogeneity complicates the interpretation of findings and may affect the generalizability of results. Specifically, the expression levels and functional roles of HULC can differ significantly among patients. To elucidate the broader patterns and clinical relevance of HULC, larger, well-powered studies are necessary. In future research, machine learning algorithms may be employed to construct predictive models capable of identifying HULC expression signatures from diverse patient-derived samples.

HULC exerts its effects through multiple molecular interactions, involving genes, RNA, and proteins. These interactions include diverse epigenetic mechanisms such as DNA methylation, histone modifications, and regulation by non-coding RNAs. The diversity of these epigenetic processes present a substantial challenge for studying the potential mechanisms of HULC in tumorigenesis. To address this, future studies should incorporate high-throughput sequencing, single-cell analysis, multi-omics integration, and large-scale sample validation, along with investigations into newly discovered epigenetic modifications.

Accurate detection and quantification of HULC require highly sensitive and specific techniques, which depend on sophisticated laboratory infrastructure and skilled personnel to ensure data quality and reproducibility. Furthermore, high-throughput technologies generate vast amounts of data, the analysis of which demands advanced bioinformatics tools and expertise. Extracting biologically meaningful insights from these datasets remains a critical challenge. Future investigations should leverage cutting-edge sequencing platforms and innovative functional assays to elucidate the oncogenic role and clinical significance of HULC in digestive system cancers.