LncRNA-DANCR Interferes With miR-125b-5p/HK2 Axis to Desensitize Colon Cancer Cells to Cisplatin vis Activating Anaerobic Glycolysis

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.

The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer

“…In the study carried out by Xiong et al (2021), they investigated the role of the lncRNA DANCR in promoting DOX resistance in CRC cells. Similar to what was reported by Shi et al [269], DANCR was overexpressed in CRC tissues and cell lines, and in resistant cells, but in cells treated with DOX instead of cisplatin as the study of Shi et al [269]. When DANCR was silenced DOX induced apoptosis increased, which resulted in decreased cell numbers in G0/G1 phase but elevated cell numbers in S and G2/M phases, while when DANCR was overexpressed, the growth of resistant cells was promoted [281].…”

“…In addition, its overexpression desensitised the colon cells to cisplatin, while this was reversed when this lncRNA was silenced. Further analyses revealed that DANCR acted as a ceRNA, being able to bind to miR-125b-5p, with the correlation between the two being negative since miR-125b-5p was downregulated when DANCR was overexpressed [269]. Moreover, overexpression of miR-125b-5p enhanced the sensitivity of cisplatin resistant cells.…”

“…The lncRNA differentiation antagonising non-coding RNA (DANCR) was investigated by Shi et al to determine its involvement in regulating cisplatin resistance in CRC [269]. DANCR was upregulated in both CRC tissues and in cisplatin resistant CRC cells.…”

“…Apart from these observations, the same study also noted an increase in glycolysis rate in the resistant cells, due to miR-125b-5p targeting the hexokinase 2 (HK2) enzyme in these cells. Shi et al went on to show a new mechanism through which cisplatin resistance developed in the colon cells, via the DANCR/miR-125b-5p/HK2 axis [269]. Another lncRNA which was shown to be upregulated in cisplatin resistant CRC cells is MIR4435-2 Host Gene (MIR4435-2HG) [270].…”

Circular RNA circVAPA promotes chemotherapy drug resistance in gastric cancer progression by regulating miR-125b-5p/STAT3 axis

“…MiRNAs are short non-coding RNAs with a length of about 22nt and can target various genes by pairing with the mRNAs at the post-transcriptional level[ 14 , 15 ]. MiR-125b-5p is a well-investigated tumor suppressor in multiple cancer models, including bladder cancer, laryngeal squamous cell carcinoma, and colon cancer[ 16 - 18 ]. Furthermore, it has been well-identified that circRNAs and miRNAs are involved in the chemotherapy resistance in GC[ 8 , 19 - 21 ].…”