Abstract
Colon cancer is one of the most prevalent malignancies that lead to high occurrence of cancer-related deaths. Currently, chemotherapies and radiotherapies remain the primary treatments for advanced colon cancer. Despite the initial effectiveness, a fraction of colon cancer patients developed cisplatin resistance, resulting in therapeutic failure. The long non-coding RNA differentiation antagonizing non-coding RNA (DANCR) has been shown to be upregulated in multiple cancers, indicating an oncogenic role of DANCR. This study aims to elucidate the roles of DANCR in regulating cisplatin (CDDP) resistance of colon cancer. We found DANCR was significantly upregulated in colon cancer tissues and cells compared with normal colon tissues and cells. DANCR was upregulated in cisplatin-resistant colon cancer cells. Moreover, overexpression of DANCR significantly desensitized colon cancer cells to cisplatin. On the other way, silencing DANCR dramatically overrode CDDP resistance of colon cancer cells. Bioinformatics prediction revealed DANCR could bind to seeding region of miR-125b-5p as a competitive endogenous RNA. This interference was further validated by luciferase assay. Moreover, we detected a negative correlation between DANCR and miR-125b-5p in colon cancer patient tissues: miR-125b-5p was clearly downregulated in colon cancer tissues and cells. Overexpression of miR-125b-5p significantly sensitized cisplatin-resistant cells. Interestingly, we observed the cisplatin-resistant cells were associated with a significantly increased glycolysis rate. We further identified glycolysis enzyme, hexokinase 2 (HK2), as a direct target of miR-125b-5p in colon cancer cells. Rescue experiments showed overexpression of miR-125b-5p suppressed cellular glycolysis rate and increased cisplatin sensitivity through direct targeting the 3′ UTR of HK2. Importantly, silencing endogenous DANCR significantly induced the miR-125b-5p/HK2 axis, resulting in suppression of the glycolysis rate and increase in cisplatin sensitivity of colon cancer cell. Expectedly, these processes could be further rescued by inhibiting miR-125b-5p in the DANCR-silenced cells. Finally, we validated the DANCR-promoted cisplatin resistance via the miR-125b-5p/HK2 axis from an in vivo xenograft mice model. In summary, our study reveals a new mechanism of the DANCR-promoted cisplatin resistance, presenting the lncRNA-DANCR–miR-125b-5p/HK2 axis as a potential target for treating chemoresistant colon cancer.
Highlights
Colorectal cancer is a commonly diagnosed cancer with poor prognosis and high mortality rate, presenting it as one of the major causes of the cancer-related death worldwide [1, 2]
Given that differentiation antagonizing non-coding RNA (DANCR) is positively associated with colon cancer, to further assess the potential functions of DANCR in cisplatin sensitivity, we transfected DANCR overexpression lentiviral vector into two colon cancer cell lines, HT-29, and SW620 (Figure 1C)
We established a cisplatin-resistant colon cancer cell line (SW480/CDDP R) via continuous exposing SW480 cells to cisplatin by gradually increased concentrations of cisplatin
Summary
Colorectal cancer is a commonly diagnosed cancer with poor prognosis and high mortality rate, presenting it as one of the major causes of the cancer-related death worldwide [1, 2]. Surgical resection is the major and traditional therapy for colorectal cancer [2]. Chemotherapy and radiotherapy are promising approaches for patients with late-stage or metastatic colorectal cancer [3]. Cisplatin (CDDP), with the capacity to induce DNA damage, is a widely used chemotherapeutic agent for effective treatments of various types of cancers [4]. Despite the initial effectiveness in colon cancer chemotherapy, a fraction of patients developed resistance to CDDP treatment, resulting in therapeutic failure [5]. Because of acquired chemoresistance, the morbidity and mortality of colorectal cancer still remain considerable [5, 6]. Investigating the molecular mechanisms underlying the drug resistance of colon cancer will contribute to improving the clinical outcomes of affected patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
