Cancer is a complex human disease with multiple risk factors that involves biological processes such as genetic mutations, chromosomal remodeling and epigenetic alterations (1). To a certain extent, early diagnosis and timely treatment are the greatest challenges in the field of oncology. As research on the roles of genomic alternations and the immune system further develops, many new biomarkers or therapeutic strategies targeted to specific molecular changes or other biological characteristics have emerged such as specific molecular agonist that enables T cells to mediate tumor killing and generating immune memory more efficiently (2–4). Despite the rapid development of cancer research, the death rate of diverse malignancies remains high due to the lack of efficient interventions. Therefore, new potential molecular biomarkers and therapeutic targets with high sensitivity and specificity need to be investigated.

Long noncoding RNAs (lncRNAs), which are over 200 nucleotides in length, are a class of endogenous and non-protein-coding RNAs (5, 6). The majority of lncRNAs are expressed in particular tissues at specific times and are broadly involved in the transcriptional or posttranscriptional regulation of the expression of coding genes, including key regulators of multiple pathways (7, 8). In recent years, a variety of cancer studies have uncovered that lncRNAs can fulfil oncogenic or tumor-suppressive functions in cancer biology (9), impacting cancer cell biological characteristics such as multiplication capacity, invasiveness and motility through diverse mechanisms (10). Hence, lncRNAs have a powerful effect on the occurrence and development of human cancers. Classified from function, there are four types of lincRNAs: signaling, guide, decoy, and scaffold lncRNAs (1, 11). Signaling lncRNAs are correlated with particular signaling pathways and their expression is often accompanied by active signaling events (9). Guide lncRNAs combine with and direct regulatory protein complexes to specific loci and then regulate downstream biological events. Decoy lncRNAs bind to the target gene promoters and interact with transcription factors or suppressor (9). Scaffold lncRNAs function as a central platform for various protein complexes to connect and target to specific location and then regulate genomic activities. Intriguingly, accumulating evidence has revealed mechanism of action between lncRNAs and another type of noncoding RNA—miRNAs (12). For example, lncRNA CDC6 accelerates breast cancer progression by directly sponging miR-215, which further regulates the expression of CDC6 (13). Thoroughly investigating the features of lncRNAs will greatly expand our current knowledge of cancer biology and provide novel perspectives for oncotherapy.

As one of the earliest oncogenic lncRNAs discovered in prostate cancer (14), PCGEM1 has received increasing attention in recent years. The PCGEM1 gene is located at chromosome 2q32.3, without protein-coding capacity (14) and lncRNA PCGEM1 was found to distribute uniformly in cell nucleus and cytoplasm (15). In the past two decades, many studies have suggested crucial functions of PCGEM1 in the initiation and progression of various cancers, such as renal carcinoma and endometrial cancer (EC) (16, 17). Through diverse functional mechanisms, PCGEM1 has a large effect on downstream genes and then regulates cancer cell proliferation, invasion and apoptosis. PCGEM1 was also reported to modulate oxaliplatin resistance in hepatocellular carcinoma (HCC) (18). PCGEM1 can influence other diseases, such as osteoarthritis and asthma (19–21). More importantly, preclinical experiments and in vitro studies have shown the tremendous clinical potential of PCGEM1.

Herein, we summarized the recent progress regarding the dysregulation and cancer-related functions of PCGEM1 in cell lines and clinical samples of different types of cancer. Furthermore, the comprehensive specific molecular mode of action and potential clinical implications of PCGEM1 will also be discussed.

In the past few years, PCGEM1 has been widely reported to be aberrantly expressed in various human cancers, such as glioma, oral carcinoma and EC. Associations between the dysregulation of PCGEM1 and clinical characteristics have also been observed in patients. In this section, we will discuss the aberrant expression of PCGEM1 in clinical samples from cancer patients with an emphasis on the correlated clinical features and cancer growth traits in tumor xenograft models ( Table 1 ).

Apart from the association between dysregulated expression profiles and clinicopathological characteristics of PCGEM1 in multiple cancers, related biological effects and diverse underlying mechanisms were also explored through in vitro and in vivo experiments. Generally, PCGEM1 facilitates oncogenic pathophysiologic processes such as cancer cell proliferation and invasion through multiple axes or key modulators. In the next section, we will review the biological roles of PCGEM1 in tumors and the underlying mechanisms of PCGEM1 functions, highlighting the upstream regulators and downstream effectors in the network model. Additionally, the comprehensive functions of PCGEM1 and pivotal molecules in various tumors are listed in Table 2 .

Biomarkers are defined as biological molecules existing in serum, other body fluids or human tissues that could be measured and assessed to indicate biological processes and disease features. Biomarkers are principally used for disease diagnosis and prognosis evaluation, prediction of the disease tendency, and evaluation of the response to treatment, facilitating the improvement of intervention measures for patients (75, 76). The search for effective biomarkers for PC has been ongoing for a few decades, and it has come a long way owing to advanced genomic technologies and tools (77, 78). However, the discovered specific biomarkers may be invalidated by tumor heterogeneity because these molecular mediators are closely correlated with cancer etiopathogenesis (79). Prostate-specific antigen (PSA) has been extensively used for PC screening and monitoring for a long time, but its sensitivity and specificity are inherently limited by the cancer concealment and nonsignificant increases in expression (80, 81). Considering these limitations, the thorough investigation of up/downstream molecules and the relation of biomarkers with tumor etiology is indispensable.

Above, we discussed the expression profiles and oncogenic roles of PCGEM1 in various tumors. As a novel noncoding RNA, it was confirmed to be overexpressed in PC, especially in African-American patients (14), and was found to be significantly associated with CRPC. The close relationship between PCGEM1 and clinical features, including tumor stage, metastasis and overall survival rate, has also been well demonstrated. Notably, PCGEM1 is highly expressed in noncancer prostate tissues of PC patients with a family history of PC (25). Xue and colleagues revealed that polymorphisms of PCGEM1 may make contribution to PCa risk in Chinese men (82). All of the above findings indicate its potential for early prevention, diagnosis and prognosis evaluation as a favorable biomarker. More encouragingly, the interaction between PCGEM1 and AR in PC has been brilliantly described (26), which provides new ideas for early detection and a novel therapeutic target for PC. From previous studies in multiple separate laboratories, there seems to be no consensus on the interaction of PCGEM1 and AR, although these controversial findings were preliminarily interpreted through in vivo and in vitro experiments (15, 26, 52, 65). The expression of PCGEM1 in peripheral blood was also measured in a study enrolling 144 patients with PC, and PCGEM1 expression was significantly higher in metastatic group than localized group. Moreover, the expression level in patients with poor prognosis was critically upregulated (83). Another study carried out in a multiracial population demonstrated that a 2-gene (PC3 and PCEGM1) expression panel in urine exosomes could differentiate aggressive PC from nonaggressive PC (27). Thus, the promising application of PCGEM1 needs more evaluation. Because of the important roles by which PCGEM1 facilitates PC progression in an AR-dependent or AR-independent manner, PCGEM1-targeted treatment is also an attractive area of study. For example, PCGEM1 silencing could increase the sensitivity of PC cells to baicalein and enzalutamide (51, 55), laying the groundwork for PC combination therapy. Further clinical trials are needed to design and assess the therapeutic effects of targeting PCGEM1. PCGEM1 is also regarded as a potential target in other tumors. For example, it could modulate oxaliplatin resistance via the miR-129-5p/ETV1 axis in HCC, indicating a promising strategy for combating HCC chemotherapy resistance (18). Currently, endoscopy and biopsy are the standard diagnostic approaches for GC, and their utility is confined to the invasiveness of the disease and limited medical resources (84). Jiang et al. (29) assessed PCGEM1 expression in GC patient serum and found that it could reflect the pathophysiological state of GC (29), demonstrating that this molecule might be a favorable indicator for GC diagnosis and prognosis.

As an important member of the lncRNA family located on chromosome 2q32, PCGEM1 has been confirmed to function as a tumor promotor in diverse tumors. In this review, we presented retrospective evidence of its upregulated expression based on data from multiple cancer cell lines and matched tumor/nontumor tissues. Additionally, tumor xenograft growth in a mouse model and clinical features in patients, such as tumor stage and metastasis, were found to be significantly associated with PCGEM1 dysregulation. Functional analysis also revealed that multiple biological effects, including proliferation, invasion and migration, apoptosis, drug resistance and metabolism of cancer cells, could be potently modulated by PCGEM1 overexpression. Thus, this oncogenic lncRNA plays a critical role in the initiation and progression of cancers. In terms of the underlying mechanisms, diverse modes of PCGEM1 action in various cancers with different regulatory factors and downstream signaling pathways or molecules have been investigated in various cancer types. Even in a given cancer type, such as PC, PCGEM1 functions in various ways, including the lncRNA-miRNA-mRNA network and interaction with transcription factors. Our comprehensive interpretation of the underlying molecular mechanism of PCGEM1 seems feasible, but some questions and challenges still exist. For example, what accounts for the differences in the PCGEM1 transcriptional process in vivo and in vitro? Are there other tumor-related factors co-acting with PCGEM1?

Overall, the exploration of PCGEM1 in the oncology field is undoubtedly in the initial stage. To comprehensively understand its biological roles at multiple tumor stages, we must perform additional studies. From the standpoint of etiology, clarification of the comprehensive signaling network of PCGEM1 will provide us with more challenges and opportunities to exploit novel strategies for early prevention, specific diagnosis, accurate treatment to improve the prognosis by targeting PCGEM1.

LL and JL designed and guided the study. YS, XG, and QZ wrote and edited the manuscript. LZ helped with reference collection. All authors read and approved the final manuscript.

This work was funded by the National Key Research and Development Program of China (2021YFC2301800), and the National Nature Science Foundation of China (U20A20343).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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