HOXB7 mediates cisplatin resistance in esophageal squamous cell carcinoma through involvement of DNA damage repair

Abstract

Background DNA damage repair is an important mechanism of platinum resistance. HOXB7 is one member of HOX family genes, which are essential developmental regulators and frequently dysregulated in cancer. Recently, its relevance in chemotherapy resistance and DNA damage repair has also been addressed. However, little is known regarding the association between HOXB7 and chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Methods The association between HOXB7 expression detected by immunohistochemisty and tumor regression grade (TRG) and long‐term survival was analyzed in 143 ESCC patients who underwent neoadjuvant chemotherapy. CCK8 assay was used to examine the effect of cisplatin in a panel of four ESCC cell lines. A stable cell strain with HOXB7 knockdown of KYSE150 and KYSE450 was established to explore the effect on cisplatin sensitivity. The interaction of HOXB7 with Ku70, Ku80 and DNA‐PKcs was determined by GST‐pull down, coimmunoprecipitation and immunofluorescent colocalization. Finally, we investigated whether disrupting HOXB7 function by a synthetic peptide HXR9 blocking the formation of HOXB7/PBX could enhance cisplatin sensitivity in vitro and in vivo. Results High expression of HOXB7 was associated with cisplatin resistance and worse chemotherapy efficacy. HOXB7 knockdown reinforced cisplatin sensitivity. It was identified that HOXB7 interacts with Ku70, Ku80 and DNA‐PKcs. HOXB7 knockdown was related to the downregulation of Ku70, Ku80 and DNA‐PKcs as well as arrested cell cycle in S phase. HOXB7 inhibition by HXR9 had a synergistic effect to improve cisplatin sensitivity. Conclusion HOXB7 may be a biomarker for the prediction of chemoresistance of ESCC and serves as a promising therapeutic target.

Long non‑coding RNA LINC00491 promotes proliferation and inhibits apoptosis in esophageal squamous cell carcinoma

“…GEO data were obtained from the GEO database. The results of CNC analysis demonstrated that 69 mRNAs were co-expressed with LINC00491, including the oncogenes thyroid hormone receptor interactor 13 (TRIP13) ( 24 ) and homeobox B7 (HOXB7) ( 25 ), which are associated with ESCC ( Fig. 3B ).…”

Differential and Prognostic Significance of HOXB7 in Gliomas

“…In vitro and in vivo studies have demonstrated that HOXB7 dysregulation may play an important role in a variety of diseases including cancer. It is aberrantly expressed in a variety of cancers, including melanoma ( Carè et al, 2001 ), colorectal cancer ( Kanai et al, 2010 ), hepatocellular carcinoma ( Huan et al, 2017 ), breast cancer ( Heideman et al, 2015 ), esophageal squamous cell carcinoma ( Zhou et al, 2020 ), intrahepatic cholangiocarcinoma ( Dai et al, 2019 ), gastric cancer ( He et al, 2017 ), pancreatic cancer ( Chile et al, 2013 ), and other tumors. However, there are few reports on the relationship between HOXB7 and gliomas.…”

“…Homeobox B7 (HOXB7), a member of the homeobox family abnormally overexpressed in a variety of solid tumors, plays an important role in proliferation, migration and invasion of tumor cells ( Carè et al, 2001 ; Kanai et al, 2010 ; Chile et al, 2013 ; Heideman et al, 2015 ; He et al, 2017 ; Huan et al, 2017 ; Dai et al, 2019 ; Zhou et al, 2020 ). Its expression is closely related to clinicopathological features, but the signaling pathways causing this phenotype have yet to be elucidated.…”

Roles of the HOX Proteins in Cancer Invasion and Metastasis

“…Cancer cells' sensitivity to this peptide is highly correlated to their HOX expression profile, albeit the subset of HOX genes which act as oncosuppressors is not affected [34]. This peptide has shown to be effective in oesophageal and oral squamous cell carcinomas [36,37], melanoma [35,38], ovarian cancer (OC) [39], breast cancer [40], meningioma [41], prostate cancer [42], and leukaemia [43]. The use of RNA interference mechanisms [44,45] and the control of HOX methylation status [46] are additional tools that can control HOX expression with therapeutic function.…”