. 2018 Aug 23;11:107. doi: 10.1186/s13045-018-0645-x

Table 2.

Overview of the dysregulated expression and functions of MT isoforms in cancer

Cancer type	MT isoforms	Expression	Functions	References
Acute nonlymphoblastic leukemia	MT	Positive	Resistance-related proteins	[182]
Acute myeloid leukemia	MT1G, MT1A	Positive	Inversely correlated with PU.1 expression	[183]
Acute myeloid leukemia	MT3	Down	Promoter hypermethylation	[154]
Adenoid cystic carcinomas of the salivary glands	MT	Up	Myoepithelial differentiation	[184]
Basal cell carcinoma	MT	Up	Infiltrative growth	[185]
	MT1, MT2	Up	Promote proliferation: Ki-67 antigen expression	[43]
	MT3	Down	Possibly based on DNA methylation	[186]
	MT3	Low to moderate expression	Carcinogenesis	[187]
Bladder carcinoma	MT	Up	Drug resistance	[188]
	MT2	Up	Cisplatin resistance	[99]
	MT3	Up	Carcinogenesis and increase tumor grade	[189]
	MT1X	Up	Correlated with tumor grade	[190]
	MT	Up	Poor survival and cisplatin resistance	[23]
Breast cancer	MT3	Up	Poor prognosis	[130]
	MT2A	Up	Increase invasiveness	[191]
	MT1E	Present in estrogen receptor (ER)-negative breast cancer	Myoepithelial differentiation and tumor invasiveness	[191]
	MT2A	Up	Modulate cell cycle via the ATM/Chk2/cdc25A signaling pathway	[39]
	MT2A	Up	Upregulation of matrix metalloproteinase (MMP)-9; enhance cell invasion and migration	[82]
	MT3	Up	Increase invasiveness	[83]
Cholangiocarcinoma	MT	Partly positive	Poor prognosis	[128]
Colonic cancer	MT	Up	Promote proliferation	[36]
	MT1F	Down	Loss of heterozygosity	[52]
	MT1G, MT1X, MT2A	Down	Associated with the depth of tumor invasion, lymph node metastasis, and tumor stage	[52]
Colorectal cancer	MT2A, MT1B, MT1F, MT1G, MT1H, MT1B, MT1F, MT1G, MT1H, MT2A	Down	Poor clinical outcome	[192]
	MT1E, MT1F, MT1G, MT1H, MT1M, MT1X MT2A	Down	Epigenetic mechanisms	[6]
	MT2A	Up	Interact with Fas-associated death domain (FADD) in NF-κB pathway to promote cell proliferation	[49]
	MT1G	Down	Colorectal cancer cell differentiation	[67]
Ductal breast cancer	MT1E	High in ER-negative cancer tissues	Mediate effector genes downstream of ER	[193]
	MT1F	Up	Influence histological differentiation	[58]
	MT2A	Up	Cell proliferation	[41]
	MT2A	Up	Chemoresistance (doxorubicin)	[59]
	MT1, MT2	Up	Increased proliferative potential	[20]
	MT3	Down	Epigenetic changes	[88]
Endometrial carcinoma	MT1, MT2	Up	Modify p53 expression	[141]
Endometrial carcinoma	MT1E	Down	Promoter hypermethylation	[143]
Esophageal adenocarcinoma	MT3	Down	DNA methylation	[152]
Esophageal squamous cell carcinoma	MT	Up	Chemoresistance to cisplatin; poor prognosis	[194]
	MT3	Down	DNA methylation	[153]
	MT1G	Down	Gene methylation	[145]
	MT1G	Down	Promoter hypermethylation	[146]
	MT1M	Down	DNA methylation; correlated with smoking duration	[195]
Gallbladder carcinoma	MT	Up	Histological dedifferentiation	[63]
Gastric carcinoma	MT3	Down	Hypermethylation	[151]
	MT1G	Up	Cisplatin resistance	[196]
	MT1X	Up	Irinotecan resistance	[103]
	MT	Up	Poor survival and high recurrence rate	[81]
	MT2A	Down	Inhibit the activation of the NF-κB pathway	[135]
	MT2A	Down	Be a potential target of miR-23a	[197]
	MT1D (MTM)	Down	Enhance migration and invasion	[198]
	MT1M, MT1JP	Down	Associated with tumor diameter, differentiation, lymphatic metastasis, distal metastasis, invasion, and tumor node metastasis (TNM) stage	[199]
Glioma	MT1E	In proportion to the motility of glioma cell	Enhance tumor proliferation, invasion, and migration through regulation of activation and expression of MMPs	[84, 85]
Hepatoblastoma	MT1G	Down	Promoter hypermethylation	[147]
Hepatocellular carcinoma	MT1F	Down	Cell growth	[200]
	MT1G	Down	Allelic loss on chromosome 16q12.1-q23.1	[155]
	MT1, MT2A	Down	Transcriptional repression: dephosphorylation of the transcription factor CCAAT/enhancer-binding protein (C/EBP) α through phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway	[25]
	MT1X, MT2A	Down	Malignant transformation of hepatocytes; local invasion; hepatitis B virus infection	[201]
	MT1G	Down	Tumor suppressor gene; promoter hypermethylation	[148]
	MT1M	Down	Increase NF-κB activity	[142]
	MT1, MT2	Down	Promoter hypermethylation and transcriptional repression; prognostic marker	[133]
	MT1M, MT1G	Down	Promoter methylation	[136]
	MT1M	Down	Poor prognosis	[134]
	MT1, MT2	Down	Associated with the disruption of circadian clock genes	[202]
	MT1H	Down	Regulate the Wnt/β-catenin signaling pathway	[8]
	MT1M	Down	Inhibit tumorigenesis	[203]
Intrahepatic cholangiocarcinoma	MT1A, MT1E, MT1F, MT1G, MT1H, MT1IP, MT1X	Down	Hypermethylation	[204]
Lung cancer	MT1A, MT2A, MT1E, MT1G	Down	Gene methylation	[205]
Large cell lung cancer	MT1F, MT1G, MT1M, MT1X	Up	Poor prognosis	[206]
Melanoma	MT	Up	Poor prognosis	[24, 125]
	MT1E	Down	DNA methylation	[144]
	MT1, MT2	Up	Intratumoural macrophage infiltration to defect host immune response and metastasis formation	[77]
Nasopharyngeal cancer	MT	Up	Cell proliferation	[21]
Non-small cell lung cancer	MT	Up	Tumor cell proliferation and short survival	[122]
	MT1H	Up	Drug resistance (cisplatin)	[207]
	MT1, MT2	Up	Promote proliferation: expressions of Ki-67 and minichromosome maintenance protein-2 (MCM-2) (positive correlation)	[40]
	MT3	Up	Pathogenesis	[208]
	MT1B, MT1F, MT1G, MT1H, MT1X	Up	Pathogenesis	[131]
	MT1F, MT2A	Up	Poor outcome	[131]
	MT1E	Down	Cell differentiation	[131]
Oral squamous cell carcinoma	MT	Up	Poor prognosis	[127]
	MT1A, MT1X, MT3, MT4	Down	Possible markers for oral carcinogenesis	[209]
	MT1G	Down	Poor survival	[209]
	MT1F	Up	Associated with tobacco use	[209]
Osteosarcoma	MT1E, MT1H, MT1X, MT2A, MT1B, MT1G, MT1L	Up	Drug resistance	[210]
Ovarian cancer	MT1, MT2	Up	Mutant p53; histological grade	[22]
	MT2A	Up	Inhibit cell death	[211]
	MT1L, MT1X, MT2A	Up	Low malignant potential or early cancer onset	[212]
Pancreatic carcinoma	MT	Partly positive	Metastasis, poor prognosis, and poor histological grade	[62]
Papillary thyroid carcinoma	MT1G	Down	Promoter hypermethylation	[149]
	MT1E, MT1G, MT1X, MT2A	Down	Promoter methylation and transcriptional repression	[7]
	MT1G	Down	Modulate the activity of the PI3K/AKT and Rb/E2F pathways	[89]
Prostate cancer	MT3	Highly variable increase	Control prostate epithelial cell growth	[213]
	MT1X	Down	Advanced prostate cancer	[214]
	MT2A	Up	Inhibit cell death	[211]
	MT3	Up	Inhibit cell growth and increase drug resistance	[53]
	MT1G	Down	Promoter hypermethylation	[150]
	MT1F, MT1M	Down	Associated with perineural invasion	[215]
	MT1H	Down	Enhance the histone methyltransferase activity of euchromatin histone methyltransferase 1 (EHMT1)	[26]
	MT2A	Down	Single nucleotide polymorphism (SNP); metal accumulation	[14]
	MT3	Depend on cell type	Increase cell proliferation, invasion, and tumorigenic activities	[104]
	MT1E	Down	DNA methylation	[10]
Renal cell cancer	MT	Up	Tumor grade	[64]
	MT2A	Up	Stimulate cellular proliferation	[216]
	MT1A, MT1G	Down	Growth arrest and induction of apoptosis	[216]
	MT1A, MT1E, MT1G, MT1H, MT1L	Down	Tumorigenesis	[217]
	MT1H, MT1G, MT2A	Down	Promoter methylation	[45]
Salivary gland adenocarcinoma	MT	Up	High immunoreactivity and microenvironment remodeling	[90]
Serous ovarian cancer	MT	Up	Diagnosis of malignancy and worse prognosis	[218]
Small cell lung cancer	MT	45% positive	P53 expression and short-term survival	[121]
Soft tissue sarcoma	MT	Up	Ki-67 expression, grade of malignancy, and prognostic appraisal	[44]
Soft tissue sarcoma	MT2A, MT1X, MT1F, MT1H	Up	Metastasis	[219]
Squamous cell carcinoma of the tongue	MT	Positive	Delay cells entering apoptosis	[220]
Squamous cell carcinoma of the tongue	MT	Positive	Correlated with depth of invasion, vascular invasion, and lymph node metastasis	[221]
Testicular cancer	MT	Up	Chemoresistance	[222]
Testicular cancer	MT	Up	Early diagnosis	[115]
Transitional cell carcinoma of the bladder	MT	Up	Poor survival	[126]