Increased RIPK4 expression is associated with progression and poor prognosis in cervical squamous cell carcinoma patients

Abstract

Aberrant expression of receptor interacting protein kinase 4 (RIPK4), a crucial regulatory protein of Wnt/β-catenin signaling, has recently been reported to be involved in several cancers. Here, we report the potential clinical implication and biological functions of RIPK4 in cervical squamous cell carcinoma (CSCC). One hundred and ninety-eight CSCC cases, 109 low-grade squamous intraepithelial lesions (LSILs), 141 high-grade squamous intraepithelial lesions (HSILs) and 63 chronic cervicitis were collected. The expression of RIPK4 was detected by immunohistochemistry (IHC), and its clinical value and oncogenic functions were further assessed. RIPK4 expression increased significantly with disease progression from 3.2% in chronic cervicitis, 19.3% in LSILs and 85.1% in HSILs to 94.4% in CSCCs (P < 0.001). Moreover, RIPK4 may serve as a useful biomarker to distinguish HSIL from chronic cervicitis/LSIL, which are two different clinical types for therapeutic procedures, with a high sensitivity and specificity (85.1% and 86.6%, respectively) and the performance improved when combined with p16INK4a. Further, RIPK4 overexpression was associated with overall (HR = 2.085, P = 0.038) and disease-free survival (HR = 1.742, P = 0.037). Knockdown of RIPK4 reduced cell migration and invasion via inhibition of Vimentin, MMP2 and Fibronectin expression in cervical cancer cells. RIPK4 might act as a potential diagnostic and independent prognostic biomarker for CSCC patients.

Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis

“…It has been shown that RIPK4 can enhance tumorigenesis by increasing Wnt signaling (Huang et al, 2013). Consistently, it has been shown that elevated expression of RIPK4 associates with the progression and poor prognosis of cervical SCC (Liu et al, 2015a). On the other hand, consistent with its role in tissue differentiation, RIPK4 loss of function has been identified in human head and neck SCC through exome sequencing (Stransky et al, 2011), and retroviral insertional mutagenesis also identified RIPK4 as a tumor suppressor in human heptocarcinogenesis (Heim et al, 2015).…”

Mutational landscape of penile squamous cell carcinoma in a Chinese population

“…Immunohistochemical analysis and Western blotting were performed according to the standard protocol 31 with the following antibodies: CASP8 (Novus, St. Louis, MO; NB100-56527), TRRAP (Biorbyt, San Francisco, CA; orb158656), TTN (Sigma, St. Louis, MO; SAB1400284), FLG (Abcam, Cambridge, UK; ab81468), CCDC168 (Abcam, ab151018), FBXW7 (Abcam, ab109617), H-RAS (Santa Cruz, Santa Cruz, CA; sc-29), PIK3CA (Abcam, ab87530), Notch1 (Cell Signaling Technology [CST], Danvers, MA; 3608), PARP (CST, 9542) and GAPDH (Sigma, G9545). The penile cancer cell line Penl1 32 was used for gene function analysis and cultured in DMEM medium with 10% fetal bovine serum.…”

Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques

“…In some instances, a common enhancer spatially co-regulates multiple genes through looping interactions with the promoters of each gene 57,[64][65][66][67][68] . In MB157 and HCC1599 TNBC cells, Notch activation promotes looping interactions involved in spatial co-regulation of the kinase RIPK4 and the serine protease TMPRSS2 ( Figures 3J and S3H), both of which are implicated in breast cancer pathogenicity [69][70][71][72][73] . Based on normalized contact tracks ( Figures 3J and S3H), Notch activation significantly increased transcript abundance and contact frequency of RIPK4 and TMPRSS2 promoters to common Notch-bound and -activated enhancers, located 155 and 150 Kb away, respectively.…”