Researchers have found that the upregulation of HOXA transcript at the distal tip (HOTTIP), an oncogene, in cholangiocarcinoma (CCA) is negatively associated with the therapeutic effects of chemotherapy and subsequent clinical outcomes, according to a study published in Frontiers in Oncology.

HOTTIP was discovered to affect the proliferation, colony formation, and apoptosis of CCA cells under the treatment of gemcitabine and cisplatin. Hence, the silencing of HOTTIP enhances sensitivity to chemotherapy treatment in CCA. 

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CCA is a primary liver cancer that ranks second only to hepatocellular carcinoma in morbidity. CCA patients are known to have a very poor prognosis because the majority of them are diagnosed when the disease is already at an advanced stage. Gemcitabine and cisplatin are standard chemotherapy drugs that are used in treating advanced CCA, although they offer only a median overall survival of less than a year.

“HOTTIP functions as a signal transmitter from higher order chromosomal configuration into chromatin codes” and “not only takes part in the regulation of development, but also displays an oncogenic role in multiple cancers like hepatocellular carcinoma, gastric cancer, and colorectal cancer,” wrote authors of this study. The role of HOTTIP in CCA is poorly understood. 

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The purpose of this study was to investigate the effects of HOTTIP on chemotherapy. Researchers analyzed CCA samples that were collected from patients through biopsy or surgery.

The results show that HOTTIP was upregulated in the serum of CCA patients compared to healthy volunteers. Patients with higher levels of HOTTIP were found to be in a more advanced stage of the disease. When HOTTIP expression was silenced in vitro, gemcitabine and cisplatin treatment was better able to impair the proliferation and colony formation of CCA cells. Apoptosis in CCA cells was also found to be magnified.

This indicates that the silencing of HOTTIP may provide new opportunities to improve the efficacy of chemotherapy in CCA. 


Gao K, Chen S, Yang X. HOTTIP enhances gemcitabine and cisplatin resistance through sponging miR-637 in cholangiocarcinoma. Front Oncol. Published online July 5, 2021. doi:10.3389/fonc.2021.664916