Abstract
Lactate dehydrogenase A (LDHA), a critical component of the glycolytic pathway, relates to the development of various cancers, including thyroid cancer. However, the regulatory mechanism of LDHA inhibition and the physiological significance of the LDHA inhibitors in papillary thyroid cancer (PTC) are unknown. Long non-coding RNA (lncRNA) plays a vital role in tumor growth and progression. Here, we identified a novel lncRNA LINC00671 negatively correlated with LDHA, downregulating LDHA expression and predicting good clinical outcome in thyroid cancer. Moreover, hypoxia inhibits LINC00671 expression and activates LDHA expression largely through transcriptional factor STAT3. STAT3/LINC00671/LDHA axis regulates thyroid cancer glycolysis, growth, and lung metastasis both in vitro and in vivo. In thyroid cancer patients, LINC00671 expression is negatively correlated with LDHA and STAT3 expression. Our work established STAT3/LINC00671/LDHA as a critical axis to regulate PTC growth and progression. Inhibition of LDHA or STAT3 or supplement of LINC00671 could be potential therapeutic strategies in thyroid cancer.
Highlights
Thyroid cancer (TC) is the most prevalent endocrine malignancy and one of the most rapidly increasing cancers around the world [1]
The results showed that only LINC00671 led to a marked decrease in both Lactate dehydrogenase A (LDHA) mRNA and protein levels in the two papillary thyroid cancer (PTC) cells (Fig. 1E and Fig. S1G)
To further confirm the effect of LINC00671 in PTC cells, we knocked down LINC00671 with the specific smart pool of silencers and found that the LDHA expression levels were significantly increased in both TPC cells (Fig. 1F)
Summary
Thyroid cancer (TC) is the most prevalent endocrine malignancy and one of the most rapidly increasing cancers around the world [1]. 10% of PTC cases dedifferentiate into the aggressive type, characterized by the metastases at early stages to the lungs (50%) and other sites with local invasion and/or distant metastasis [3, 4] To this end, it is urgent and essential to identify novel treatment targets for PTC and understand the molecular mechanisms during PTC initiation and progression. Energy metabolism reprogramming is widely accepted as a novel hallmark of cancer, characterized by high glycolysis regardless of the presence of abundant oxygen [5, 6] This glycolysis process is usually accompanied by glucose uptake and lactate production, as well as ATP generation, facilitating tumor growth and progression. STAT3/LINC00671/LDHA axis regulates glycolysis, tumor growth, and lung metastasis of PTC both in vitro and in vivo. Our work establishes STAT3/LINC00671/LDHA as a novel and critical axis regulating PTC growth and progression
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