Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.

Pkm基因的可变剪接（alternative splicing）可产生丙酮酸激酶（pyruvate kinase）的PKM1与PKM2两种同工型，且PKM2的表达与胚胎发生、组织再生及癌症发生密切相关。为探究PKM2在个体发育与组织稳态中的功能需求，我们构建了生殖系PKM2敲除小鼠（Pkm2-/-）。出乎意料的是，尽管PKM2是多数野生型成年组织中的主要表达同工型，但我们发现Pkm2-/-小鼠可正常存活且具备生育能力。由此可知，PKM2并非胚胎发育或出生后发育所必需的因子。PKM2的缺失会导致原本表达PKM2的组织中出现PKM1的代偿性表达。值得注意的是，PKM2缺失会以高外显率自发诱发肝细胞癌（hepatocellular carcinoma, HCC），同时伴随系统性代谢的进行性改变，具体表现为全身性葡萄糖稳态失衡、炎症反应及肝脂肪变性。因此，除了在癌症代谢中发挥作用外，PKM2还可通过非细胞自主机制调控全身性代谢稳态与炎症反应，从而预防肝细胞癌的发生。