A Critical Role of Peptidylprolyl Isomerase A Pseudogene 22/microRNA-197-3p/Peptidylprolyl Isomerase A Axis in Hepatocellular Carcinoma

Abstract

The burden of hepatocellular carcinoma (HCC) worldwide is increasing over time, while the underlying molecular mechanism of HCC development is still under exploration. Pseudogenes are classified as a special type of long non-coding RNAs (lncRNAs), and they played a vital role in regulating tumor-associated gene expression. Here, we report that a pseudogene peptidylprolyl isomerase A pseudogene 22 (PPIAP22) and its parental gene peptidylprolyl isomerase A (PPIA) were upregulated in HCC and were associated with the clinical outcomes of HCC. Further investigation revealed that PPIAP22 might upregulate the expression of PPIA through sponging microRNA (miR)-197-3p, behaving as competing endogenous RNA (ceRNA). PPIA could participate in the development of HCC by regulating mRNA metabolic process and tumor immunity based on the functional enrichment analysis. We also found a strong correlation between the expression levels of PPIA and the immune cell infiltration or the expression of chemokines, especially macrophage, C-C motif chemokine ligand 15 (CCL15), and C-X-C motif chemokine ligand 12 (CXCL12). Our findings demonstrate that the PPIAP22/miR-197-3p/PPIA axis plays a vital role in the progression of HCC by increasing the malignancy of tumor cells and regulating the immune cell infiltration, especially macrophage, through CCL15-CCR1 or CXCL12-CXCR4/CXCR7 pathways.

Clinical and Prognostic Value of PPIA, SQSTM1, and CCL20 in Hepatocellular Carcinoma Patients by Single-Cell Transcriptome Analysis

“…In breast cancer, the PPIA/CrkII axis modulates host antitumor immune escape [31]. In HCC, hypoxia increases immune infiltration through the PPIAP22/miR-197-3p/PPIA axis [32].…”

Comprehensive Genomic Characterization Analysis Identifies an Oncogenic Pseudogene RP11-3543B.1 in Human Gastric Cancer

“…For example, Chen et al found that pseudogene PRELID1P6 was over-expressed in glioma and promoted glioma progression by affecting the cellular localization of hnRNPH1, thereby protecting hnRNPH1 from ubiquitin-mediated degradation which led to up-regulated TRF2 expression and activated the Akt/mTOR pathway ( Xi et al, 2021 ). In addition, highly expressed pseudogene PPIAP22 promotes hepatocellular carcinoma progression via up-regulating PPIA expression by acting as a ceRNA for miR-197-3p ( Gu et al, 2021 ). Moreover, our previous study revealed that pseudogene DUXAP10 is over-expressed in gastric cancer, and promoted cell proliferation and invasion via interacting with EZH2 and LSD1 to repress LATS1 transcription ( Xu et al, 2018 ).…”

Noncoding RNA-mediated macrophage and cancer cell crosstalk in hepatocellular carcinoma

“…Further study found that PPIAP22 may act as a ceRNA by sponging miR-197-3p to relieve repression of its parental gene peptidylprolyl isomerase A (PPIA). 184 Similar to PPIAP22, upregulation of PPIA is also associated with tumor size and poor patient survival and has been shown to promote tumor growth. 184 , 230 The expression levels of PPIAP22 or PPIA were correlated with the infiltration levels of tumor-infiltrating immune cells (TIICs), such as T cells, dendritic cells, and macrophages, and with the expression of several chemokines, including C-C motif chemokine ligand 15 (CCL15) and C-X-C motif chemokine ligand 12 (CXCL12).…”

“… 184 Similar to PPIAP22, upregulation of PPIA is also associated with tumor size and poor patient survival and has been shown to promote tumor growth. 184 , 230 The expression levels of PPIAP22 or PPIA were correlated with the infiltration levels of tumor-infiltrating immune cells (TIICs), such as T cells, dendritic cells, and macrophages, and with the expression of several chemokines, including C-C motif chemokine ligand 15 (CCL15) and C-X-C motif chemokine ligand 12 (CXCL12). 184 Chemokines are likely also involved in the lncRNA HOTAIR-mediated relationship in HCC.…”

“… 184 , 230 The expression levels of PPIAP22 or PPIA were correlated with the infiltration levels of tumor-infiltrating immune cells (TIICs), such as T cells, dendritic cells, and macrophages, and with the expression of several chemokines, including C-C motif chemokine ligand 15 (CCL15) and C-X-C motif chemokine ligand 12 (CXCL12). 184 Chemokines are likely also involved in the lncRNA HOTAIR-mediated relationship in HCC. HOTAIR was upregulated in HCC tissues and associated with poor prognosis of patients.…”