HOXB9 mediates resistance to chemotherapy and patient outcomes through the TGFβ pathway in pancreatic cancer

// Naokazu Chiba 1 , Shigeto Ochiai 1 , Takahiro Gunji 1 , Toshimichi Kobayashi 1 , Toru Sano 1 , Koichi Tomita 1 and Shigeyuki Kawachi 1 1 Department of Digestive and Transplantation Surgery, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan Correspondence to: Naokazu Chiba, email: nchiba0632@yahoo.co.jp Keywords: HOXB9; pancreatic cancer; epithelial mesenchymal transition; TGFβ Received: March 04, 2022 Accepted: April 28, 2022 Published: May 25, 2022 Copyright: © 2022 Chiba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Background: Although HOXB9 induces tumor proliferation and chemoresistance in several cancer cells, little is known in pancreatic ductal adenocarcinoma (PDAC). In the present study, increased expression of HOXB9 in PDAC was associated with the induction of angiogenic factors and poor overall survival through the TGFβ pathway. Taken together, these results suggested that HOXB9 expression in PDAC could be a surrogate marker in clinical treatment. Methods: In vitro , angiogenic factors, TGFβ signature, Epithelial Mesenchymal Transition (EMT) marker, and chemoresistance were examined in PDAC cell lines by HOXB9 knockdown system. And the reverse effect was confirmed by using TGFβ1 recombinant. Furthermore, in clinical specimens, the correlation between HOXB9 expression and TGFβ signature was analyzed, and the relationship with clinical outcomes were investigated. Results: HOXB9 expression regulated the expression of TGFβ1 signature, angiogenic factors, and EMT markers in vitro , and TGFβ1 recombinant made the reverse effect of these results. And HOXB9 expression regulated the resistance to chemotherapy (Gemcitabine and nab-Paclitaxel) and stem cell population. Moreover, increased HOXB9 expression was significantly associated with poor disease-free survival the prognosis for overall survival. And, a significant positive correlation was observed between HOXB9 expression and several TGFβ signatures in clinical specimens. Conclusions: In conclusion, HOXB9 expression could mediate angiogenesis, EMT, and cancer stemness through the TGFβ pathway, thereby resulting in chemoresistance and poor overall outcomes in patients with pancreatic cancer. Our results suggested that HOXB9 may clinically serve as a novel surrogate biomarker.