The Multifaceted Role of Signal Peptide-CUB-EGF Domain-Containing Protein (SCUBE) in Cancer

Abstract

Signal peptide, CUB, and EGF-like domain-containing proteins (SCUBE) are secretory cell surface glycoproteins that play key roles in the developmental process. SCUBE proteins participate in the progression of several diseases, including cancer, and are recognized for their oncogenic and tumor suppressor functions depending on the cellular context. SCUBE proteins promote cancer cell proliferation, angiogenesis, invasion, or metastasis, stemness or self-renewal, and drug resistance. The association of SCUBE with other proteins alters the expression of signaling pathways, including Hedgehog, Notch, TGF-β/Smad2/3, and β-catenin. Further, SCUBE proteins function as potential prognostic and diagnostic biomarkers for breast cancer, renal cell carcinoma, endometrial carcinoma, and nasopharyngeal carcinoma. This review presents key features of SCUBE family members, and their structure and functions, and highlights their contribution in the development and progression of cancer. A comprehensive understanding of the role of SCUBE family members offers novel strategies for cancer therapy.

Keywords: SCUBE; angiogenesis; biomarkers; metastasis; oncogene; signaling; tumor suppressor.

Figure 1

(A) Location of SCUBE1, SCUBE2, and SCUBE3 on their respective chromosomes and common arrangement of structural domains in SCUBE proteins. SCUBE family proteins as surface glycoprotein. They are composed of an N-terminal region, signal peptide sequence (SPS), nine EGF-like repeats (E), a spacer region (SR), three cysteine rich repeats (CR), a CUB domain, and a C-terminal region. (B) Structural discrepancy of SCUBE family protein. Grey represents whole protein structure, black EGF-like repeats-Ca binding site, and red is the CUB domain.

Figure 2

Expression of SCUBE family members in various human tumors. (A) SCUBE1, (B) SCUBE2, and (C) SCUBE3 expression in different cancer types in comparison to adjacent normal tissue. Data extracted from TCGA database determined by tumor immune estimation resource (TIMER) presented as log2-TPM. TPM denotes transcript count per million.

Figure 3

Genomic alteration in SCUBE family genes in various human cancers. Mutation and CNA data for SCUBE analyzed from 32 studies and 10,967 patient’s samples using cBioportal. (A) Data show the highest SCUBE1 gene alteration in skin cutaneous melanoma; (B) SCUBE2 shows the highest gene alterations in uterine corpus endometrial carcinoma; (C) SCUBE3 exhibits overexpression in skin cutaneous melanoma. Gene alteration is reported as amplification, deep deletion, mutation, structural variation, or multiple alterations.

Figure 4

Protein–protein interaction network with SCUBE family and other proteins on STRING database. These interactions with other proteins were experimentally studied. (A) SCUBE1; (B) SCUBE2; (C) SCUBE3.

Figure 5

Mechanism of SCUBE family in cancers and cancer stem cells in a contextual manner. VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; PI3K/Akt, phosphoinositide 3-kinase/protein kinase B; EMT, epithelial–mesenchymal transition; BCa, breast-cancer; Shh, sonic hedgehog; Ptch, patched homolog; Smo, smoothened; Gli, Gli family zinc finger; MMP-2/9, matrix metalloproteinase 2/9; Stat3, signal transducer and activator of transcription factor 3; TGF, transforming growth factor-β; NSCLC, nonsmall-cell lung cancer; LC, lung cancer; BlC, bladder cancer; PCOS, polycystic ovary syndrome; RCC, renal-cell cancer; GC, gastric cancer.