HER4 Promotes Osteosarcoma Progression and Predicts Poor Prognosis through the PTEN-PI3K/AKT Pathway
Authors: Chuan Zhang
Kun Ma
Journal: Journal of Cancer (2022)
Discipline: CLINICAL MEDICINE
Keywords: HER4; PI3K/mTOR pathway; PTEN; invasion; osteosarcoma
Affiliations: Luoyang Orthopaedic Hospital of Henan Province & Orthopaedic Hospital of Henan Province, Luoyang, Henan 471002, China.

Abstract:  Studies have reported a relationship between human epidermal growth factor receptor 4 (HER4), a ubiquitously expressed and unique member of the ErbB family, and clinicopathological features of osteosarcoma. However, further investigation is warranted. HER4 expression was analyzed by quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. The relationship between HER4 expression and the prognosis of patients with osteosarcoma was determined by constructing a Kaplan-Meier curve. Cell viability and proliferation were investigated by MTT and colony formation assays. The mechanism underlying HER4-modulated proliferation and invasion/migration of osteosarcoma cells was determined by short hairpin RNA (shRNA) interference, colony formation, migration, invasion, and western blotting experiments. Spheroid formation assay and CD133+ cell populations were used to examine HER4-induced stem-like traits. The present findings revealed that HER4 was overexpressed in both osteosarcoma cells and tissues. Moreover, this overexpression was associated with high Enneking stage, metastasis, and recurrence. Sh-HER4 showed obviously suppressed cell viability, colony formation, and invasion/migration. In addition, knockdown of HER4 markedly attenuated the spheroid size and proportion of CD133-positive cells, as well as the expression of stemness markers. Sh-HER4 also reduced the tumor size, downregulated the expression of phosphorylated-PI3K (p-PI3K) and p-AKT, and increased that of p-phosphatase and tensin homolog (p-PTEN) in mouse tissue. From a mechanistic perspective, HER4 knockdown activated p-PTEN and suppressed p-PI3K and p-AKT expression. HER4 promoted osteosarcoma progression through inactivation of the PTEN-PI3K/AKT pathway. Taken together, the results indicate that HER4 represents a novel target in osteosarcoma progression and stemness modulation, and may be of value for the development of treatments against osteosarcoma. 

Retracted: No

PubPeer comments:
 There appears to be some images in this paper which appear in at least one other paper (in some cases after rotation), seemingly with a set of 4 papers involved. There seems to be two papers with common authors, but the others seem unrelated. Of note, the Journal of Cancer (2019) was retracted u201cdue to concerns on multiple image duplications as identified by PubPeer users. The corresponding author has been contacted by the journal, and the authors expressed apology for their negligence and mistakes in this paper.u201d Figure 2D (upper left) Journal of Cancer (2022) doi: 10.7150 jca.62787 Received 15 May 2021 https: pubpeer.com publications B4EEF4C364C4CFD562DDCB029F965F Figure 3C (lower left) OncoTargets and Therapy (2020) doi:10.2147 ott.s217745 Received 30 May 2019 https: pubpeer.com publications 6A7FD31BAF2A764D5A0FC4CD928807 Figure 2J (upper right) Cell Proliferation (2020) doi: 10.1111 cpr.12833 Received: 14 January 2020 https: pubpeer.com publications E895DBD3B6277460E277A43926A185 Figure 2B (lower right) Journal of Cancer (2019) RETRACTED doi: 10.7150 jca.29931 Received 12 December 2018 https: pubpeer.com publications F8CD809499CDCEC1BB53327CE808A0 *** ![file] , 
 #1 Update: the Oncotargets Therapy paper has been retracted. The Journal of Cancer is investigating. ,