SSRP1 promotes colorectal cancer progression and is negatively regulated by miR‐28‐5p

Abstract

In this study, microarray data analysis, real‐time quantitative PCR and immunohistochemistry were used to detect the expression levels of SSRP1 in colorectal cancer (CRC) tissue and in corresponding normal tissue. The association between structure‐specific recognition protein 1 (SSRP1) expression and patient prognosis was examined by Kaplan‐Meier analysis. SSRP1 was knocked down and overexpressed in CRC cell lines, and its effects on proliferation, cell cycling, migration, invasion, cellular energy metabolism, apoptosis, chemotherapeutic drug sensitivity and cell phenotype‐related molecules were assessed. The growth of xenograft tumours in nude mice was also assessed. MiRNAs that potentially targeted SSRP1 were determined by bioinformatic analysis, Western blotting and luciferase reporter assays. We showed that SSRP1 mRNA levels were significantly increased in CRC tissue. We also confirmed that this upregulation was related to the terminal tumour stage in CRC patients, and high expression levels of SSRP1 predicted shorter disease‐free survival and faster relapse. We also found that SSRP1 modulated proliferation, metastasis, cellular energy metabolism and the epithelial‐mesenchymal transition in CRC. Furthermore, SSRP1 induced apoptosis and SSRP1 knockdown augmented the sensitivity of CRC cells to 5‐fluorouracil and cisplatin. Moreover, we explored the molecular mechanisms accounting for the dysregulation of SSRP1 in CRC and identified microRNA‐28‐5p (miR‐28‐5p) as a direct upstream regulator of SSRP1. We concluded that SSRP1 promotes CRC progression and is negatively regulated by miR‐28‐5p.

MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy

“…Hence, targeting N4BP1 or TNIP1 will result in strong activation of NFkB signaling, which in turn boosts MHC-I expression. Indeed microRNA (miR) 28-5p is an inhibitor of N4BP1 and has been demonstrated to act as a tumor suppressor in many cancer types, including colorectal cancer, renal cell carcinoma, and hepatocellular carcinoma [ 65 , 66 , 67 ]. In addition, MiR-1180 and miR-486 have also been demonstrated to induce NFkB activation via targeting of several inhibiting players of the NFkB pathway, including Cezanne, A20, and TNIP1-3 [ 68 , 69 ].…”

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

“…The second FACT subunit SSRP1-M was initially thought to lack histone binding (185), however it was later shown to bind H3-H4 as well as H2A-H2B (186). In vivo the SSRP1 subunit enhanced xenograft tumor growth/proliferation and SSRP1 overexpression in vitro promoted EMT (187). Mechanistically, miRNA-28-5p was implicated in upstream negative regulation of SSRP1 (187), however given the discovery of PH domains within Spt16 and SUPT16H-H3/H4 binding, it is reasonable to suggest that SSRP1 promotes EMT via epigenetic regulation of key genes, albeit further research is required.…”

Long intergenic noncoding RNA01134 accelerates hepatocellular carcinoma progression by sponging microRNA-4784 and downregulating structure specific recognition protein 1

“…Moreover, this result was further validated by the luciferase reporter assays. SSRP1 has been considered as an oncogene in a multiple of human malignancies including HCC [16][17][18]. Thus, we asked whether miR-4784 functioned as a tumor suppressor by targeting SSRP1 in HCC cells.…”

“…The bioinformatics analysis indicated that SSRP1 mRNA might be a potential target of miR-4784 (Figure 4(a)). Of interest, several studies have showed that SSRP1 acts as an oncogene in multiple malignancies including HCC [16][17][18].…”