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P- Reviewer: Chowdhury P, Shah A S- Editor: Song XX L- Editor: A E- Editor: Lu YJ
FIGURE LEGENDS
Figure 1 The variants and the corresponding protein structures of cluster of differentiation 74. The upper panel
illustrates the corresponding position among genomic region, NCBI reference sequence number and reference protein accession, exon (green box) and intron (green line) localization of DNA, transcripts (light blue box), and protein (pink box) of the three cluster of differentiation 74 (CD74) variants. The lower panel, CD74 variants contains three regions including intracellular, transmembrane and extracellular regions with the indicated functional domains and identified residues for post-translational modification. Variant 2 transcripts two isoforms, p33 and p35 caused by the alternative start site. Variant 1 transcripts two isoforms, p41 and p43, with an exon 6b-encoded thyroglobulin type I domain to interact with cathepsin. Variant 3 lacks exon 5, 6, and 6b, which translates truncated trimerization domain and truncated macrophage
migration inhibitory factor (MIF)-binding domain and remains only the CLIP region to function as major histocompatibility complex class II mask. The amino acid residues refer to human variant 2 (p35).
Figure 2 The canonical function of cluster of differentiation 74 in the immune system. Cluster of differentiation 74 (CD74) is present on endoplasmic reticulum (ER) where it can interact with
major histocompatibility complex class Ⅱ (MHC class Ⅱ) and contribute to antigen presentation. Once synthesized, CD74 self-assembles as a trimer and serves as a scaffold onto which nascent MHC class Ⅱ assemble. After trafficking to the late endosome, CD74 is cleaved into a small peptide, CLIP, to block the peptide binding cleft of MHC class Ⅱ, prevent premature binding of antigenic peptides, and direct the MHC class Ⅱ complex to the endosomal pathway. The MHC class Ⅱ molecules with bound antigenic peptides are then exported to the surface of the antigen presenting cell for presentation of foreign peptides to CD4+ T cells.
Figure 3 The function of cluster of differentiation 74 in the cancer development. (Ⅰ) Membrane associated-CD74 is involved in modulating the expression of a variety of genes which involved cell proliferation, invasion and survival through interacting with CD44, CXCR1, CXCR2 or CXCR4 followed by activation of the signaling cascades in a MIF-dependent manner. (Ⅱ) After MIF stimulation, CD74 releases its intracellular domain, CD74-ICD. The CD74-ICD translocates from cytoplasm into nucleus and functions as a
transcription modulator. (Ⅲ) The CD74-ROS1 fusion protein with one (minor form) or two (major form) transmembrane regions and one kinase domain, promotes novel invasiveness pathway through the
phosphorylation of the extended synaptotagmin-like protein, E-Syt1.
MIF: Macrophage migration inhibitory factor; CXCR: Chemokine (C-X-C motif) receptor; PKA: Protein kinase A; PK(C-X-C: Protein kinase (C-X-C; GEF:
Guanine nucleotide exchange factor; Ras: Ras oncogene; Rho: Ras homolog family member; MLCK: Myosin light chain kinase; FAK:
Focal adhesion kinase; Raf-1: RAF proto-oncogene serine/threonine-protein kinase; MEK: Mitogen-activated serine/threonine-protein kinase kinase; ERK:
Extracellular signal-regulated kinase; PI3K: Phosphoinositide 3-kinase; NF-B: Nuclear factor-kappaB; TAF(II)105: Transcription initiation factor TFIID 105 kDa subunit; ROS-1: C-ros oncogene 1; E-Syt1: Extended synaptotagmin-like protein 1; Bcl-2: B-cell
lymphoma 2; Bcl-XL: B-cell lymphoma-extra large; cPLA2: Cytosolic phospholipase A2; ELK1: Member of ETS oncogene family; Ets: V-ets erythroblastosis virus E26 oncogene; PGE2: Prostaglandin E2; Tap63:
Tumor protein p63; IL-8: Interleukin 8; VEGF-D: Vascular endothelial growth factor D.
Table 1 Expression levels and clinical significance of cluster of differentiation 74 in human cancers
Cancer type Event Method Ref
Renal cell cancer CD74 was detected in 53 of 60 (88.3%) renal cell cancer tissues IHC [90, 91]
CD74 is a useful diagnostic marker for distinguishing clear cell RCC from chromophobe and oncocytoma RCC
IHC [92]
CD74 was upregulated in 34 of 40 (85.0%) of clear cell RCC tissues compared with the corresponding normal kidney tissues, and the expression level was positively correlated with VEGF-D (Pearson’s correlation, r = 0.65, P < 0.001)
Quantitative re
Differential expression of CD74 was found in atypical malignant fibrous histiocytoma (90%
positive) and fibroxanthoma (10% positive), suggesting that CD74 may be a marker of tumor progression
IHC [93]
CD74 was detected in 88% (15/17) of thymic carcinomas, 70% (14/20) of invasive thymomas, but only 33% (9/27) of benign thymomas (9/27), suggesting that CD74 is a useful marker for the classification of thymic epithelial neoplasms
IHC [94]
Colorectal cancer A linear increase of CD74 expression was found in the progression from low- to high-grade invasive cancer tissues
IHC [95]
High levels of CD74 were detected in 23 of 156 (15.0%) curatively resected colorectal cancer tissues
IHC [96]
CD74 was increased in dysplastic epithelial cells in 47 of 55 (85%) human colorectal adenomas, with CD74 and MIF protein levels together predicting increasing dysplasia in individual adenomas (P = 0.003)
IHC [97]
Gastric cancer CD74 was detected in 48 of 126 (38.1%) gastric cancer tissues, and the expression was negatively correlated with the depth of invasion and HLA-DR expression. The patients with detectable CD74 show poor surgical outcomes (P < 0.05)
CD74 was detected in 39 of 58 (67.2%) gastric carcinoma tissues, showing significant correlation with the differentiation of gastric carcinoma (P < 0.05)
IHC IHC
[98]
[99]
Breast cancer The expression of CD74 was significantly more abundant in invasive or metastatic tumors than in ductal carcinoma in situ (P = 0.02 and P = 0.05, respectively)
SAGE [100]
CD74 was detected in 468 of 580 (80.7%) breast cancer tissues, and was related to lymph node metastasis and triple-negative breast cancer (P = 0.01 and 0.001). In addition, CD74 expression had a linear correlation with lymph node metastasis and triple-negative breast cancer (P = 0.02 and 0.001)
IHC [101]
Stat1 and CD74 overexpression is co-dependent and linked to increased invasion and lymph node metastasis in triple-negative breast cancer
LC-MS/MS, IH C
[102]
CD74 expression was increased in high-grade, invasive urothelial carcinoma of the bladder [103]
Multiple myeloma CD74 was detected in 19 of 22 (86.4%) multiple myeloma tissues IHC [69]