Deciphering the effects of PYCR1 on cell function and its associated mechanism in hepatocellular carcinoma

Abstract

Overexpression of pyrroline-5-carboxylate reductase 1 (PYCR1) has been associated with the development of certain cancers; however, no studies have specifically examined the role of PYCR1 in hepatocellular carcinoma (HCC). Based on The Cancer Genome Atlas expression array and meta-analysis conducted using the Gene Expression Omnibus database, we determined that PYCR1 was upregulated in HCC compared to adjacent nontumor tissues (P < 0.05). These data were verified using quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry analysis. Additionally, patients with low PYCR1 expression showed a higher overall survival rate than patients with high PYCR1 expression. Furthermore, PYCR1 overexpression was associated with the female sex, higher levels of alpha-fetoprotein, advanced clinical stages (III and IV), and a younger age (< 45 years old). Silencing of PYCR1 inhibited cell proliferation, invasive migration, epithelial-mesenchymal transition, and metastatic properties in HCC in vitro and in vivo. Using RNA sequencing and bioinformatics tools for data-dependent network analysis, we found binary relationships among PYCR1 and its interacting proteins in defined pathway modules. These findings indicated that PYCR1 played a multifunctional role in coordinating a variety of biological pathways involved in cell communication, cell proliferation and growth, cell migration, a mitogen-activated protein kinase cascade, ion binding, etc . The structural characteristics of key pathway components and PYCR1-interacting proteins were evaluated by molecular docking, and hotspot analysis showed that better affinities between PYCR1 and its interacting molecules were associated with the presence of arginine in the binding site. Finally, a candidate regulatory microRNA, miR-2355-5p, for PYCR1 mRNA was discovered in HCC. Overall, our study suggests that PYCR1 plays a vital role in HCC pathogenesis and may potentially serve as a molecular target for HCC treatment.

Survival and clinicopathological significance of PYCR1 expression in cancer: A meta-analysis

“…According to the established search strategy, 89 literatures were initially screened. After exclusion according to the literature screening flow chart (Figure 1), eight clinical research literatures were finally included, and the studied population consisted of 728 cases (9)(10)(11)(12)(13)(14)(15)(16). The literature was of high quality and without significant publication bias.…”

Functional Impact of a Cancer-Related Variant in Human Δ1-Pyrroline-5-Carboxylate Reductase 1

“… 24 Additionally, small molecule inhibitors of PYCR1 have been shown to impair the spheroidal growth of MCF10A H-RAS V12 breast cancer cells 25 and proliferation of myelogenous erythroleukemic K562 and epithelial breast cancer MDA-MB-231 cell lines. 26 Recent therapeutic studies have shown that silencing of PYCR1 reduces the progression and proliferation of the cancer cells 27 , 28 and leads to the induction of apoptosis. 11 Increased apoptosis with loss of PYCR1 has also been reported in other diseases such as autosomal recessive cutis laxa.…”

Shikonin induces apoptosis and autophagy via downregulation of pyrroline-5-carboxylate reductase1 in hepatocellular carcinoma cells

“…One research group based on bioinformatics technology, reported that the PYCR1 was overexpressed in HCC cells. It played a multifaceted regulatory assignment in various biological pathways, such as cell communication, cell growth, cell migration, mitogen-activated protein kinase cascade, etc [ 33 ]. Another group observed that PYCR1 gene silencing could inhibit the proliferation of hepatoma cells, promote apoptosis, and significantly inhibit the volume and size of transplanted tumors in nude mice by regulating the JNK/IRS1 pathway [ 10 ].…”