Reprogramming of cellular metabolism is a hallmark of cancers. Cancer cells more readily use glycolysis, an inefficient metabolic pathway for energy metabolism, even when sufficient oxygen is available. This reliance on aerobic glycolysis is called the Warburg effect, and promotes tumorigenesis and malignancy progression. The mechanisms of the glycolytic shift in tumors are not fully understood. Growing evidence demonstrates that many signal molecules, including oncogenes and tumor suppressors, are involved in the process, but how oncogenic signals attenuate mitochondrial function and promote the switch to glycolysis remains unclear. Here, we summarize the current information on several main mediators and discuss their possible mechanisms for triggering the Warburg effect.

The sweet trap in tumors: aerobic glycolysis and potential targets for therapy

Cytology-based Papanicolaou test on and primary HPV screening have been widely used in the identification of cervical cancer and precancerous lesions, which is of great significance for the prevention and treatment of cervical cancer. Patients diagnosed as ASCUS/LSIL usually need follow-up because some of them may develop into CIN2+. The consequences of women positive for HPV vary from person to person; some of them may progress into cervical dysplasia, reversible forms of precancerous lesions, and eventually invasive cervical cancer. Therefore, it is necessary to establish an effective biomarker to triage different patients according to the preliminary screening results. p16 acts as a cell cycle regulatory protein that induces cell cycle arrest, and Ki-67 is a cell proliferation marker. Under physiological conditions, they could not co-express in the same cervical epithelial cells. The co-expression of these two molecules suggests a deregulation of the cell cycle mediated by HR-HPV infection and predicts the presence of high-grade cervical epithelial lesions. There is increasing evidence that p16/Ki-67 dual-staining cytology can be used as an alternative biomarker, showing overall high sensitivity and specificity for identifying high-grade CIN and cervical cancer. In this review, we discuss the significance of p16/Ki-67 dual-staining and summarize its application in the screening and triaging of cervical cancer and precancerous lesions.

Enhanced glycolysis under normoxic conditions is known as aerobic glycolysis or the Warburg effect and is a hallmark of many tumors. Viral infection may also induce aerobic glycolysis as it is required for replication and survival. Tumor viruses inducing aerobic glycolysis and lactate production during latent infection suggest a potential role of virus-induced glycolysis in tumorigenesis. Virus or virus-encoded proteins regulate glucose uptake and lactate export, increase the activity of glycolytic enzymes, and modulate glucose metabolic signals. Accumulating evidence suggests that virus-induced glycolysis may facilitate cell growth, transformation, migration, and invasion, but its significance in tumorigenesis remains unclear. We summarize the effects of oncogenic viruses on the metabolic shift to aerobic glycolysis and discuss the possible association of this metabolic reprogramming with tumor development and progression.

Estrogen signaling influences the development and progression of ovarian tumors, but the underlying mechanisms are not well understood. In a previous study we demonstrated that impairment of estrogen receptor alpha (ERα)-mediated olfactomedin 4 (OLFM4) expression promotes the malignant progression of endometrioid adenocarcinoma, and we identified OLFM4 as a potential target of miR-486-5p. In this study we investigated the role of OLFM4 in ovarian serous adenocarcinoma. Ovarian serous adenocarcinoma tissues had reduced OLFM4 expression. Expression of OLFM4 was positively correlated with ERα expression, and estrogen (E2) treatment in ovarian cancer cells induced OLFM4 expression in an ERα-dependent manner. In contrast to ERα, miR-486-5p levels were inversely correlated with OLFM4 expression in ovarian serous adenocarcinoma. Ovarian cancer cells transfected with miR-486-5p mimics showed decreased OLFM4 mRNA expression, and ovarian cancer cells treated with E2 showed reduced cellular miR-486-5p levels. OLFM4 knockdown enhanced proliferation, migration, and invasion by ovarian cancer cells. Low expression of OLFM4 was also associated with high tumor FIGO stage and poor tumor differentiation. These results suggest OLFM4 is downregulated by miR-486-5p, which contributes to ovarian cancer tumorigenesis. Conversely, estrogen receptor signaling downregulates miR-486-5p and upregulates OLFM4 expression, slowing the development and progression of ovarian cancer.

Endometrial adenocarcinoma is the most common tumour of the female genital tract in developed countries, and oestrogen receptor (ER) signalling plays a pivotal role in its pathogenesis. When we used bioinformatics tools to search for the genes contributing to gynecological cancers, the expression of Olfactomedin 4 (OLFM4) was found by digital differential display to be associated with differentiation of endometrial adenocarcinoma. Aberrant expression of OLFM4 has been primarily reported in tumours of the digestive system. The mechanism of OLFM4 in tumuorigenesis is elusive. We investigated OLFM4 expression in endometrium, analysed the association of OLFM4 with ER signalling in endometrial adenocarcinoma, and examined the roles of OLFM4 in endometrial adenocarcinoma. Expression of OLFM4 was increased during endometrial carcinogenesis, linked to the differentiation of endometrioid adenocarcinoma, and positively related to the expression of oestrogen receptor‐α (ERα) and progesterone receptor. Moreover, ERα‐mediated signalling regulated expression of OLFM4, and knockdown of OLFM4 enhanced proliferation, migration and invasion of endometrial carcinoma cells. Down‐regulation of OLFM4 was associated with decreased cumulative survival rate of patients with endometrioid adenocarcinoma. Our data suggested that impairment of ERα signal‐mediated OLFM4 expression promoted the malignant progression of endometrioid adenocarcinoma, which may have significance for the therapy of this carcinoma.