Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers

Table 1 Summary of the literature supporting an oncogenic role of caldesmon

	Cell/cancer type	Findings	Research method	Ref.
1	Colorectal cancer	L-CaD was expressed in colorectal cancer and liver metastasis, compared with normal tissue. L-CaD was associated with a poor response to chemotherapy. L-CaD was associated with resistance to 5-Fu treatment and caused an increase in p21 and cleaved-PARP and a decrease in the expression of NF-κB and p-mTOR in vitro	Clinical, functional	Kim et al[39], 2012
2	Colon, bladder, and prostate	CALD1 may indicate cancer-related splicing events. CALD1 was identified as a tumor-specific splicing variant in colon and urinary bladder cancer tissue samples	Bioinformatics, and experimental	Thorsen et al[40], 2008
3	Colorectal cancer	CALD1 was upregulated and associated with M2 macrophage infiltration, angiogenesis, and TGF-β in stage III/IV mismatch-proficient colorectal cancer. High expression of CALD1 was significantly correlated with transendothelial migration. Cancer cell proliferation, invasion, and migration abilities were suppressed after reducing CALD1 expression in vitro	Clinical, bioinformatics, functional	Zheng et al[41], 2021
4	Colorectal cancer-early-onset	CALD overexpressed in early-onset colorectal cancer	Bioinformatics, in silico, clinical	Zhao et al[42], 2019
5	Rectal cancer	CALD1 overexpressed in nonresponders to chemotherapy	Clinical	Chauvin et al[43], 2018
6	Colorectal cancer	Novel l-CaD isoforms produced by alternative splicing of CALD1 played a role in colorectal cancer metastasis	Bioinformatics, in silico	Lian et al[44], 2020
7	Gastric cancer	CALD1 is a novel target of TEA domain family member 4 that is involved in cell proliferation and migration	Bioinformatics, in silico	Lim et al[45], 2014
8	Gastric cancer	High expression of CALD1 is associated with poor overall survival and with immune infiltration in gastric cancer	Bioinformatics, in silico	Liu et al[46], 2021
9	Breast cancer, study of ER	Silencing of ER in MCF7 cells upregulated CALD1, concomitantly with the acquisition of a new phenotype that encompasses increased growth rates, loss of cell-to-cell adhesion and a redistribution of the cytoskeletal components, resulting in increased motility	Functional analysis, basic study	Al Saleh et al[47], 2011
10	Breast cancer-ER-positive	ANXA1 and CALD1 were associated with downregulation of ER via activation of NF-κB signaling, which blocks apoptosis and allows cancer cells to become independent of estrogen. ANXA1 and CALD1 proteins are independent markers for tamoxifen therapy outcome (resistance) and are associated with fast tumor progression	Clinical, association, pathway analysis	De Marchi et al[48], 2016
11	Normal mouse mammary cells	The expression level and phosphorylation state of CaD increase as a function of time after induction of EMT by TGF-β1, and these changes in CaD correlate with increased focal adhesion number and size and increased cell contractility	Functional analysis, basic study	Nalluri et al[49], 2018
12	Bladder cancer	L-CaD overexpression in primary nonmuscle invasive bladder cancer is significantly associated with tumor progression. L-CaD is implicated in increased cell motility and invasive characteristics through morphological changes in bladder cancer cells	Clinical, functional	Lee et al[50], 2015
13	Bladder cancer	CaD was identified as one of the proteins with significant differential expression between bladder cancer tissue and normal urothelial tissue, using antibody microarray profiling of tissue samples	Clinical	Lee et al[51], 2015
14	Bladder cancer	Low CALD1 in tumor is associated with a good prognosis	Bioinformatics, in silico	Liu et al[52], 2019
15	Bladder cancer	CALD1 was correlated with aggressive features and poor overall survival. CALD1 promotes tumor cell growth, migration, invasion, and the cell cycle; it inhibits tumor cell apoptosis in vitro and in vivo. CALD1 expression was positively correlated with JAK/STAT activation resulting in PD-L1 overexpression	Clinical, functional	Li et al[53], 2021
16	Bladder cancer	CALD1 was overexpressed in CAFs, as well as macrophages and T cells in the microenvironment of bladder tumors and was associated with oncogenic features	Bioinformatics, functional	Du et al[54], 2021
17	Bladder cancer	MIR100HG inhibits the expression of miR-142-5p, resulting in the upregulation of CALD1 and acquisition of aggressive features in bladder cancer	Clinical, bioinformatics, functional	Zhang et al[55], 2021
18	Lung cancer	CaD is overexpressed in brain metastases of lung cancer	Clinical, expression	Zhang et al[56], 2014
19	NSCLC	Activation of the anaphase-promoting complex by p53 induces a state of dormancy in NSCLC cells after 5-Fu. Subsequently, EMT and CaD upregulation were associated with dormant cancer stem cells	Experimental, functional	Dai et al[57], 2016
20	Squamous cell carcinoma of oral cavity	CaD expression is associated with a poor prognosis in patients with oral squamous cell carcinoma. CaD increased invasion and migration and was elevated in patients’ serum	Clinical, functional	Chang et al[58], 2013
21	Nasopharyngeal carcinoma	Bone marrow-derived mesenchymal stem cells secreted nitric oxide in the nasopharyngeal carcinoma tumor environment, which resulted in translocation of CaD to the podosome in a Ca2+/calmodulin manner in tumor cells and promotion of their invasion and metastatic ability	Functional	Zhang et al[59], 2014
22	Glioma	CALD1 was upregulated in neoplastic cells. CALD1 was associated with a progressive vessel architecture. CALD1 may serve as marker of glioma progression	Clinical, functional	Cheng et al[60], 2021
23	Glioma, patients’ serum	The serum level of l-CaD was significantly higher in the group of glioma patients as compared to any of the other brain tumor groups	Clinical	Zheng et al[61], 2005
24	Glioma-associated blood vessels	Splicing variants of CALD1 are differentially expressed in glioma neovascularization versus normal brain microvasculature. The mis-splicing of CALD1 correlated with the breakdown of tight junctions among vascular endothelial cells	Expression, functional	Zheng et al[62], 2004
25	Endothelial cells	L-CaD is involved in the migration of endothelial cells and/or endothelial progenitor cells into human neoplasms (gliomas, breast cancers, renal cell carcinomas) where they contribute to tumor angiogenesis	Expression, functional	Zheng et al[63], 2007
26	Kidney epithelial cells, mouse mammary cells	CaD is activated and upregulated upon TGF-β induction of EMT. CALD1 overexpression is a key component in TGF-β-driven EMT	Functional	Morita et al[64], 2007
27	Not specified	CaD maintains newly polymerized actin in a distinct state that has a higher affinity for the Arp2/3 complex	Functional	Jensen et al[65], 2012

h-CaD: High-molecular-weight caldesmon; l-CaD: Low-molecular weight caldesmon; EMT: Epithelial to mesenchymal transition; TGF: Transforming growth factor; CaD: Caldesmon; NSCLC: Non-small-cell lung cancer; 5-Fu: 5-fluorouracil; CAFs: Cancer-associated fibroblasts; JAK/STAT: Janus kinase/signal transducers and activators of transcription; PD-L1: Programmed death ligand 1; NF-κB: Nuclear factor kappa B; p-mTOR: Phosphorylated mammalian target of rapamycin; ER: Estrogen receptor.

Table 2 Summary of the literature supporting a tumor suppressor role of caldesmon

	Cell/cancer type	Findings	Research method	Ref.
1	Colorectal cancer	An alternatively spliced form of CALD1 was decreased in tissues from colorectal tumor as compared to adjacent normal tissues	Bioinformatics, in silico	Liu et al[66], 2018
2	Gastric cancer	CaD is decreased in metastasis-derived gastric cancer cell lines. Knockdown of CaD resulted in an increase in cell migration and invasion	Proteomics, clinical, functional	Hou et al[67], 2013
3	Breast, colorectal, and thyroid cancer cells	The ectopic expression of l-CaD reduced the number of podosomes/invadopodia and suppressed cell invasion	Basic, functional	Yoshio et al[68], 2007
4	Breast cancer, and rat aorta cell lines	PKGI-β enhances breast cancer cell motility and invasive capacity by phosphorylating CaD. Knockdown of endogenous CaD in MDA-MB-231 breast cancer cells had pro-migratory and pro-invasive effects	Basic, functional	Schwappacher et al[69], 2013
5	Prostate cancer	Leupaxin phosphorylates CaD leading to its downregulation, and this downregulation of CaD increased migration and invasion of prostate cancer cells	Basic experimental	Dierks et al[70], 2015
6	Vascular smooth muscle cells and NIH 3T3 fibroblast cells	CaD upregulation mediates p53 suppression of Src-induced podosome and rosette formation and cellular invasiveness. The study is based on normal cells and whether or not it applies to malignancy remains to be clarified	Basic, functional	Mukhopadhyay et al[71], 2009

PKGI-β: cGMP-dependent protein kinase I; CaD: Caldesmon; l-CaD: Low-molecular weight caldesmon.