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

Table 1 Genetic and epigenetic alterations in hypoxia-related enzymes correlated with the development and progression of gastrointestinal cancers

Cancer type	Gene	Type of change	Consequence	Model	Ref.
HCC and CCA	PHD2	Haplo-deficiency	Stabilized HIF-1 and promoted carcinogenesis and progression of HCC/CCA	Mice	[66,67]
HCC	PHD3	Reduced tumor level	Correlated with elevated levels of HIF-1, aggressive tumor behavior, and a poor prognosis in HCC patients	HCC patient	[68]
GC	PHD3	Reduced tumor level	Correlated negatively with tumor size and stage, as well as HIF-1 and VEGF expression	GC patient	[69,70]
GC	PHD2	Reduced tumor level	Correlated with shortened overall survival	GC patient	[71]
CRC	PHD1-3	Reduced tumor level	Although not correlated with HIF-1 expression, PHD2 was the only factor found to be associated with unfavorable overall survival	CRC patient	[72]
PAC	PHD1-3	Increased tumor level	PHD1-3 expression was elevated, and specifically PHD3 expression was found to be associated with unfavorable overall disease-specific survival	PAC patient	[73]
PAC	VHL	Promoter methylation or deletion of VHL	Correlated with decreased VHL expression and poor prognosis	PAC patient	[74]
CRC	VHL	VHL mutation	Elevated cytoplasmic expression of HIF-1 in tumors	CRC patient	[75]
HCC	VHL	Reduced tumor level	Negative VHL expression was correlated with an unfavorable prognosis	HCC patient	[76]

ESCA: Esophageal cancer; GC: Gastric cancer; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; PAC: Pancreatic cancer; CRC: Colorectal cancer; PHD: Prolyl hydroxylase; VHL: Von Hippel-Lindau tumor suppressor.