High expression of RPL27A predicts poor prognosis in patients with hepatocellular carcinoma

Liver cancer which mainly includes hepatocellular carcinoma (HCC) (75–85%) and intrahepatic cholangiocarcinoma (10–15%) ranks seventh in the incidence and fifth in mortality of cancers in the world [1]. Although many prevention measures such as hepatitis B virus (HBV) vaccination have been taken and treatment methods have been continuously enriched, the increasing trend of morbidity and mortality of HCC has not been effectively curbed. HCC, as one of the three most common and highest mortality cancers in the digestive system, has been a focus of public health worldwide for a long time [2]. Early detection, early diagnosis, and early treatment are very important for the management of HCC, and effective biomarkers may be one of the breakthroughs.

Cancer cells tend to have strong proliferative ability and high metabolic levels. Protein, as the executor of biological function, is related to the occurrence and progression of cancer. The ribosome which is composed of ribosome RNAs (rRNA) and ribosomal proteins (RPs) plays an important role in intracellular protein biosynthesis, and RPs genes are the most highly expressed genes in most cell types, especially in cancer cells [3‐5]. The abnormal expression of RPs in some cancers can promote tumor progression such as proliferation and metastasis and could act as a tumor biomarker [6‐9]. RPL27A, as one kind of large subunit RPs, belongs to the universal ribosomal protein uL15 family and is closely correlated with some cancers, such as breast cancer and colorectal cancer [10, 11]. Weighted gene co-expression network analysis and multi-dataset verification showed RPL27A was highly expressed in HCC [12], but there were no further studies to explore the value of RPL27A in HCC.

In this study, we took full advantage of The Cancer Genome Atlas (TCGA) database and tissue microarray (TMA) to analyze the role of RPL27A in evaluating the prognosis of patients with HCC. We performed co-expression gene analyses, function enrichment analyses, and immune cell infiltration analyses to explore the role of RPL27A in HCC.

With the application of public health measures such as HBV immunization, treatment of chronic HBV and HCV, and reduction of aflatoxin exposure, and the continuous development of treatment technology for HCC, human beings seem to be increasingly optimistic in the face of HCC [2, 21‐23]. However, the global burden caused by HCC is still an arduous challenge, attributed to the large patient number, alcoholism, obesity, diabetes, nonalcoholic fatty liver disease, and other non-viral factors [2, 23]. HCC patients are often at an advanced stage when they are diagnosed, and they have a poor prognosis in the world with a very poor 5-year survival rate of only 18% and a 5-year recurrence rate of more than 60% [1, 2, 23‐25]. Effective biomarkers, targeted therapy, and immunotherapy may be breakthroughs in the treatment of HCC, which have become hot research fields.

We found that the expression of RPL27A was significantly increased in a variety of cancers, suggesting that RPL27A may play an important role in the occurrence and development of cancers. Many studies have confirmed that RPL27A could be a potential biomarker of lung cancer, triple-negative breast cancer, squamous cervical cancer, colorectal cancer, and KIRC [8, 10, 11, 26‐28]. We found that the expression level of RPL27A in HCC tissues was significantly higher than that in normal tissues. Our results showed that the high expression of RPL27A was related to the late stage and high grade of HCC, so RPL27A may be considered as a complementary biomarker of the occurrence and development for patients with HCC. Furthermore, we found that the prognosis of the high RPL27A expression group was worse than that of the low RPL27A expression group, and RPL27A could perform better than the AJCC stage in evaluating the prognosis of patients with HCC. Therefore, RPL27A could play a good auxiliary role and addition in the follow-up of patients with HCC.

To explore the possible mechanism of RPL27A in HCC, we analyzed the co-expression genes of RPL27A and the relationship between RPL27A and TP53 mutation. We found these genes mainly enriched the ribosome pathway and were mainly involved in viral gene expression, viral transcription, NMD, and proteins localization to endoplasmic reticulum (ER). NMD is a very conservative mRNA surveillance pathway to ensure the stability and quality of transcripts [29]. However, some cancers can exploit NMD to inactivate tumor suppressor genes, and NMD is involved in tumor adaptation to the harsh tumor microenvironment (TME), such as various stresses including hypoxia and reactive oxygen species [30‐32]. The imbalance of RPs in cancer may be involved in the pathogenesis of ER stress [33]. In addition, active transcription and translation of HBV favor its replication and are crucial in its pathogenic and carcinogenic mechanism [34]. In this study, all hub genes from the co-expression gene analysis of RPL27A in HCC belong to RPs. Many studies also supported the role of our hub genes in the occurrence and development of HCC [35‐40]. Furthermore, we found the HCC patients with TP53 mutation had significantly higher expression level of RPL27A and co-expression genes of RPL27A could regulate the activity of the ubiquitin-protein transferase. TP53 as one of the most important tumor suppressor genes is involved in cell differentiation, cell cycle regulation, and apoptosis, and TP53 loss-of-function is associated with cancer progression and poor prognosis in HCC patients [41]. Mutation, NMD, and ubiquitin can cause the loss of tumor suppressor function of TP53 [42‐44]. In short, RPL27A might affect HCC by the above direct or indirect pathways which could be directions of HCC research in the future.

Immune microenvironment is one important part of TME, and immune escape mechanism is one of the most important hallmarks of cancer [45]. In recent years, immunotherapy has shown satisfactory results in some cancers and has become a promising method for cancer treatment, including immune checkpoint modulators and adoptive immune cells [46]. We found that RPL27A expression was related to a variety of immune cells in HCC, including B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. Studies have shown that tumor-infiltrating immune cells can behave as either tumor-promoting or tumor-suppressive, possibly associated with the dysfunction of immune cells caused by themselves or tumors [46, 47]. Regulatory B cells, a subset of B cells, are associated with advanced stage and poor prognosis and can mediate immune escape of HCC [48, 49]. Many studies have found that CD4 + T cells are closely related to the occurrence and development of HCC, and the injury or depletion of CD4 + T cells can promote the above processes [50, 51]. Like CD4 + T cells, CD8 + T cell dysfunction can promote the growth and metastasis of HCC and is closely related to the prognosis of patients with HCC [52, 53]. In addition, tumor-associated macrophages are associated with drug resistance, cancer progression, and poor prognosis, including HCC [54‐56]. Altogether, RPL27A might affect HCC by immune infiltration, but further research are needed to confirm it.

Currently, this study and our understanding of RPL27A in HCC have several limitations. First, this study mainly used several online databases to explore the possible mechanism of the effect of RPL27A on HCC, but lack of further studies in vitro or in vivo to verify our hypotheses. Second, although this study through several online databases and TMA showed that RPL27A may be a prognostic marker for patients with HCC, more basic research and large sample clinical studies should be performed to further confirm if it was to be used for patients. In the future, we will extend the present studies to explore the role of RPL27A in HCC.

In this study, we discussed the role of RPL27A in HCC from multiple angles and speculated that it may become a biomarker in the diagnosis, treatment, and follow-up of patients with HCC, but further studies are required to verify it.