Hypoxia Induces Drug Resistance in Colorectal Cancer through the HIF-1α/miR-338-5p/IL-6 Feedback Loop

Abstract

Hypoxia is associated with poor prognosis and therapeutic resistance in cancer patients. Accumulating evidence has shown that microRNA (miRNA) plays an important role in the acquired drug resistance in colorectal carcinoma (CRC). However, the role of miRNA in hypoxia-induced CRC drug resistance remains to be elucidated. Here, we identified a hypoxia-triggered feedback loop that involves hypoxia-inducible transcription factor 1a (HIF-1a)-mediated repression of miR-338-5p and confers drug resistance in CRC. In this study, the unbiased miRNA array screening revealed that miR-338-5p is downregulated in both hypoxic CRC cell lines tested. Repression of miR-338-5p was required for hypoxia-induced CRC drug resistance. Furthermore, we identified interleukin-6 (IL-6), which mediates STAT3/Bcl2 activation under hypoxic conditions, as a direct miR-338-5p target. The resulting HIF-1a/miR-338-5p/IL-6 feedback loop was necessary for drug resistance in colon cancer cell lines. Using CRC patient samples, we found miR-338-5p has a negative correlation with HIF-1a and IL-6. Finally, in a xenograft model, overexpressing miR-338-5p in CRC cells and HIF-1a inhibitor PX-478 were able to enhance the sensitivity of CRC to oxaliplatin (OXA) via suppressing the HIF-1a/miR-338-5p/IL-6 feedback loop in vivo. Taken together, our results uncovered an HIF-1a/ miR-338-5p/IL-6 feedback circuit that is critical in hypoxiamediated drug resistance in CRC; targeting each member of this feedback loop could potentially reverse hypoxia-induced drug resistance in CRC.

Hypoxia and Macrophages Act in Concert Towards a Beneficial Outcome in Colon Cancer

“…Nevertheless, no impact in the pro-inflammatory markers IL-6 and TNF-α was observed. Interestingly, it has been recently described that HIF and IL-6 expression is increased in colorectal tumors, being both markers positively correlated [36]. In fact, we observed a slight increase in IL-6 secretion levels at 1% O 2 , although without statistical significance.…”

The Roles of Hypoxia-Inducible Factors and Non-Coding RNAs in Gastrointestinal Cancer

“…Under hypoxic conditions, HIF-1α mediates miR-338-5p downregulation, which is associated with hypoxia-induced drug resistance by regulating its direct target, IL-6. Furthermore, miR-338-5p overexpression and HIF-1α inhibitors have been shown to reduce CRC drug resistance to oxaliplatin in vivo [58].…”

“…Bcl-2 [56] miR-338-5p Reduces hypoxia-induced drug resistance by regulating IL-6. IL-6 [58] lncRNA HOTAIR Regulates tumor growth under hypoxic conditions in CRC (HRE region in lncRNA promoter 1 ). [59] miR- [15][16] Regulates tumor metastasis and angiogenesis (Indirect target of HIF-2α 1 ).…”

Exosomal microRNA‑210 is a potentially non‑invasive biomarker for the diagnosis and prognosis of glioma

“…A range of miRNAs has been reported as tumor suppressors or oncogenes for the irreplaceable mechanism in tumor initiation and progression, and as therapeutic targets (10,11). Increasing evidence supports the idea that aberrant miRNA expression serves important roles in tumor hypoxia and is associated with HIF-1α (12,13). HIF-1α is involved in multidrug resistance by regulating miR-27 in gastric cancer cells (14).…”

“…CA9 is a transmembrane glycoprotein with enzymatic activity that is located on the cell surface and is inducible by hypoxia (19). Therefore, CA9 has been identified as a potential target for cancer treatment, as it is enriched in hypoxic niches of neoplastic tissues (12).…”