The dysregulation of long non-coding RNAs (lncRNAs) plays a crucial role in the development and progression of various cancers by affecting multiple biological processes and signaling pathways. LncRNAs are involved in regulating gene expression, chromatin remodeling, and interaction with other cellular molecules, which can lead to oncogenesis when dysregulated. Aberrant expression of lncRNAs can influence cancer cell proliferation, apoptosis, migration, and invasion. For example, Zhu et al. identified key lncRNAs associated with chemoresistance in multiple cancers, noting that these dysregulated lncRNAs can alter the sensitivity of cancer cells to chemotherapy by modulating drug response pathways. This highlights the role of lncRNA in therapy resistance, which is a significant challenge in cancer treatment (41). Additionally, lncRNAs can mediate their effects through epigenetic modifications. Zhao et al. explored the landscape of epigenetically dysregulated lncRNAs in breast cancer subtypes and found that these lncRNAs contribute to subtype-specific tumorigenesis by altering DNA methylation and histone modifications at enhancer elements. This epigenetic dysregulation is crucial for maintaining cancer cell identity and promoting malignancy (42). Moreover, lncRNAs can act as competing endogenous RNAs (ceRNAs), sponging microRNAs (miRNAs) and thereby preventing them from inhibiting their target messenger RNAs (mRNAs). Wang et al. (2021) identified the lncRNA DCST1-AS1 as a key regulator in endometrial cancer progression. This lncRNA promotes tumor growth by sponging miR-665 and miR-873-5p, which leads to the upregulation of oncogenes HOXB5 and CADM1, facilitating cancer cell proliferation and invasion (43).
Environmental factors also contribute to the dysregulation of lncRNAs. Wang et al. (2021) reviewed how exposure to environmental carcinogens, such as metal carcinogens and polycyclic aromatic hydrocarbons, leads to the aberrant expression of lncRNAs. These dysregulated lncRNAs can disrupt normal cellular processes and promote carcinogenesis, providing insights into the mechanisms of environmental carcinogenesis (44).
Our study showed the possible roles of lncRNAs PLCE1-AS2 and LINC01605 in the “Organelle biogenesis and maintenance” signaling pathway. Specifically, PLCE1-AS2 and LINC01605 modulate the “Cilium assembly” process through the regulation of RPGR mRNA and its protein interactome. Organelle biogenesis and maintenance play pivotal roles in the development of GC, primarily through the mechanisms of endoplasmic reticulum (ER) stress and autophagy. The endoplasmic reticulum is crucial for protein folding and secretion, and its disruption leads to ER stress, which has been implicated in the progression and treatment responses of GC. Previous studies have shown that ER stress activates pathways that either restore cellular homeostasis or lead to cell death, influencing tumor dynamics (45). Additionally, autophagy, another cellular maintenance process, is responsible for degrading damaged organelles and has complex roles in cancer, sometimes supporting the survival of cancer cells and other times promoting cell death. Disruptions in autophagy pathways are linked to the pathogenesis and metastasis of gastric tumors (46). Overall, these cellular maintenance systems are crucial in the development and progression of gastric cancer, offering potential targets for therapeutic intervention.
Cilium assembly plays a significant role in the development of GC through various mechanisms. It acts as a crucial cellular antenna, regulating signal transduction that influences cell proliferation, differentiation, and migration (47). The deregulation of cilium assembly contributes to the progression of various cancers, including GC. For example, the primary cilium's role in signaling pathways, such as Hedgehog and Wnt, which are vital for cellular communication and tumor progression, is well-documented (48). Restoration of proper cilium function has been noted to suppress proliferation in certain cancer cells, suggesting a potential therapeutic target. Moreover, defects in the ciliary assembly are linked to a broader range of diseases, indicating the cilium's pivotal role in cellular health and disease states.
RPGR plays a critical regulatory role in organelle biogenesis and maintenance, particularly within the context of cilium assembly. As a key component in the intraflagellar transport (IFT) process, RPGR is essential for the proper assembly and function of the primary cilium, acting as a guanine nucleotide exchange factor (GEF) that facilitates the trafficking of proteins across the connecting cilium (49). This action ensures the maintenance and correct function of photoreceptors, integral to vision. Previous studies indicated that RPGR interacts with multiple ciliopathy proteins such as RPGRIP1L and CEP290, which underscores its role in cilium stability and highlights its impact on overall cellular health when dysfunctional (50). Furthermore, RPGR's involvement in organizing microtubule transport within the cilia emphasizes its role in the dynamic equilibrium required for cilium maintenance and cell viability, critical for preventing severe visual impairments due to photoreceptor structural dysfunction (51). Dysregulation of PLCE1-AS2 and LINC01605 may disturb the normal process of Cillium assembly and Organelle biogenesis and increase the risk of GC.
Previous studies
In comparison to the upregulation of PLCE1-AS2 and LINC01605 in GC samples, several other lncRNAs exhibit diverse expression patterns in GC. For instance, lincRNA-p21 is significantly downregulated in GC tissues, suggesting a tumor suppressor role by affecting cell cycle control and tumorigenicity (52). Conversely, SNHG1 is notably upregulated in GC, and its increased expression is linked to poor prognosis and enhanced tumor proliferation and invasion (53). Additional lncRNAs such as HOTAIR, HULC, and MALAT1 also exhibit altered expression in GC. HOTAIR is upregulated and associated with enhanced cell proliferation and invasion (54). HULC is upregulated, and its silencing enhances chemotherapy-induced apoptosis in GC cells (55). MALAT1 modulates chemoresistance via autophagy-related pathways (56).
These findings indicate that while PLCE1-AS2 and LINC01605 are upregulated, contributing to GC pathogenesis, other lncRNAs like lincRNA-p21 are downregulated, acting as tumor suppressors, and several others like SNHG1, UCA1, HOTAIR, HULC, and MALAT1 are upregulated, enhancing tumor progression and chemoresistance. This diversity in expression patterns underscores the complex regulatory roles of lncRNAs in GC.