Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly

Table 2 Defects in cytochrome c oxidase subunits correlated with bioenergetic alterations and the growth or progression of gastrointestinal cancers

Type	Gene	Type of defect	Consequence	Model	Ref.
GC	Full COX complex	Increased expression	Correlated with poor prognosis	GC patient	[83]
CRC	Full COX complex	Increased expression	May be involved in the initiation of carcinogenesis, but not in cancer progression	CRC patient	[84]
ESCA	MTCO1	Increased expression	There is no correlation with clinical variables or survival	ESCA patient	[86]
GC	MTCO1	Increased expression	Correlated with gastric tumorigenesis, de-differentiation, and distant metastasis, but showed no significant correlation with prognosis	GC patient	[87,88]
HCC	MTCO1	Reduced expression	Correlated with postoperative prognosis	HCC patient	[89]
CCA	MTCO1	Reduced expression	Reduced MTCO1 correlates with increased VDAC1 expression but not with other clinicopathological factors	CCA patient	[90]
HCC	MTCO3	Increased expression	HBx interacted with MTCO3, leading to an increase in MTCO3 expression levels and an enhancement in OXPHOS activity	Cell line	[91,92]
CRC	MTCO1	Genetic variation	The Gly125Asp substitution in MTCO1 correlated with an increased risk of CRC and caused proton leak in COX	CRC patient	[93,94]
GC	MTCO3	Genetic variation	Polymorphisms at mtDNA positions 9540 and 9548 correlated with an increased risk of GC	GC patient	[95]
HCC	MTCO3	Genetic variation	Polymorphisms at mtDNA position 9545 correlated with an increased risk of HCC	HCC patient	[96]
ESCA	COX4I1	Expression silenced	Promotes alterations in cellular bioenergetics and increases cancer cell aggressiveness	ESCA Cell line	[99]
ESCA	COX5B	Expression silenced	Promotes alterations in cellular bioenergetics and increases cancer cell aggressiveness	ESCA Cell line	[99]
HCC	COX5B	Increased in tumor	Correlated with prognosis, regulated bioenergetic alterations, and influenced cell proliferation, tumor growth, and migration	HCC patient, cell line, mouse model	[100]
CRC	COX5B	Reduced in tumor	Correlated with prognosis, modulated COX activity, and controlled cell proliferation, apoptosis, and response to chemotherapy	CRC patient and cell line	[101,102]
CRC	COX4I2	Increased in tumor	Promoted cell proliferation, migration, tumorigenesis, and angiogenesis	CRC patient and cell line	[103]
PAC	COX6C	Increased expression	Modulated COX activity and cell proliferation	PAC cell line	[104]
PAC	COX6B2	Increased in tumor	Correlated with prognosis, and modulated cancer cell metastatic potential, and altered bioenergetic homeostasis	PCA patient and cell line	[105]

COX: Cytochrome c oxidase; GI: Gastrointestinal; ESCA: Esophageal cancer; GC: Gastric cancer; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; PAC: Pancreatic cancer; CRC: Colorectal cancer; MTCO1: Mitochondrially encoded cytochrome c oxidase I; MTCO2: Mitochondrially encoded cytochrome c oxidase II; MTCO3: Mitochondrially encoded cytochrome c oxidase III; COX4I1: Cytochrome c oxidase subunit 4I1; COX4I2: Cytochrome c oxidase subunit 4I2; COX5B: Cytochrome c oxidase subunit 5B; COX6C: Cytochrome c oxidase subunit 6C; COX6B2: Cytochrome c oxidase subunit 6B2.